An Anti-Human ICAM-1 Antibody Inhibits Rhinovirus-Induced Exacerbations of Lung Inflammation

Human rhinoviruses (HRV) cause the majority of common colds and acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Effective therapies are urgently needed, but no licensed treatments or vaccines currently exist. Of the 100 identified serotypes, ∼90% bind domain 1 of human intercellular adhesion molecule-1 (ICAM-1) as their cellular receptor, making this an attractive target for development of therapies; however, ICAM-1 domain 1 is also required for host defence and regulation of cell trafficking, principally via its major ligand LFA-1. Using a mouse anti-human ICAM-1 antibody (14C11) that specifically binds domain 1 of human ICAM-1, we show that 14C11 administered topically or systemically prevented entry of two major groups of rhinoviruses, HRV16 and HRV14, and reduced cellular inflammation, pro-inflammatory cytokine induction and virus load in vivo. 14C11 also reduced cellular inflammation and Th2 cytokine/chemokine production in a model of major group HRV-induced asthma exacerbation. Interestingly, 14C11 did not prevent cell adhesion via human ICAM-1/LFA-1 interactions in vitro, suggesting the epitope targeted by 14C11 was specific for viral entry. Thus a human ICAM-1 domain-1-specific antibody can prevent major group HRV entry and induction of airway inflammation in vivo

Multi-spacecraft study of the solar wind at solar minimum: Dependence on latitude and transient outflows

Context: The recent launches of Parker Solar Probe, Solar Orbiter (SO), and BepiColombo, along with several older spacecraft, have provided the opportunity to study the solar wind at multiple latitudes and distances from the Sun simultaneously. Aims: We take advantage of this unique spacecraft constellation, along with low solar activity across two solar rotations between May and July 2020, to investigate how the solar wind structure, including the heliospheric current sheet (HCS), varies with latitude. Methods: We visualise the sector structure of the inner heliosphere by ballistically mapping the polarity and solar wind speed from several spacecraft onto the Sun’s source surface. We then assess the HCS morphology and orientation with the in situ data and compare this with a predicted HCS shape. Results: We resolve ripples in the HCS on scales of a few degrees in longitude and latitude, finding that the local orientations of sector boundaries were broadly consistent with the shape of the HCS but were steepened with respect to a modelled HCS at the Sun. We investigate how several CIRs varied with latitude, finding evidence for the compression region affecting slow solar wind outside the latitude extent of the faster stream. We also identified several transient structures associated with HCS crossings and speculate that one such transient may have disrupted the local HCS orientation up to five days after its passage. Conclusions: We have shown that the solar wind structure varies significantly with latitude, with this constellation providing context for solar wind measurements that would not be possible with a single spacecraft. These measurements provide an accurate representation of the solar wind within ±10° latitude, which could be used as a more rigorous constraint on solar wind models and space weather predictions. In the future, this range of latitudes will increase as SO’s orbit becomes more inclined

Rhesus TRIM5α disrupts the HIV-1 capsid at the inter-hexamer interfaces

TRIM proteins play important roles in the innate immune defense against retroviral infection, including human immunodeficiency virus type-1 (HIV-1). Rhesus macaque TRIM5α (TRIM5αrh) targets the HIV-1 capsid and blocks infection at an early post-entry stage, prior to reverse transcription. Studies have shown that binding of TRIM5α to the assembled capsid is essential for restriction and requires the coiled-coil and B30.2/SPRY domains, but the molecular mechanism of restriction is not fully understood. In this study, we investigated, by cryoEM combined with mutagenesis and chemical cross-linking, the direct interactions between HIV-1 capsid protein (CA) assemblies and purified TRIM5αrh containing coiled-coil and SPRY domains (CC-SPRYrh). Concentration-dependent binding of CC-SPRYrh to CA assemblies was observed, while under equivalent conditions the human protein did not bind. Importantly, CC-SPRYrh, but not its human counterpart, disrupted CA tubes in a non-random fashion, releasing fragments of protofilaments consisting of CA hexamers without dissociation into monomers. Furthermore, such structural destruction was prevented by inter-hexamer crosslinking using P207C/T216C mutant CA with disulfide bonds at the CTD-CTD trimer interface of capsid assemblies, but not by intra-hexamer crosslinking via A14C/E45C at the NTD-NTD interface. The same disruption effect by TRIM5αrh on the inter-hexamer interfaces also occurred with purified intact HIV-1 cores. These results provide insights concerning how TRIM5α disrupts the virion core and demonstrate that structural damage of the viral capsid by TRIM5α is likely one of the important components of the mechanism of TRIM5α-mediated HIV-1 restriction. © 2011 Zhao et al

Modulating signaling networks by CRISPR/Cas9-mediated transposable element insertion

In a recent past, transposable elements (TEs) were referred to as selfish genetic components only capable of copying themselves with the aim of increasing the odds of being inherited. Nonetheless, TEs have been initially proposed as positive control elements acting in synergy with the host. Nowadays, it is well known that TE movement into host genome comprises an important evolutionary mechanism capable of increasing the adaptive fitness. As insights into TE functioning are increasing day to day, the manipulation of transposition has raised an interesting possibility of setting the host functions, although the lack of appropriate genome engineering tools has unpaved it. Fortunately, the emergence of genome editing technologies based on programmable nucleases, and especially the arrival of a multipurpose RNA-guided Cas9 endonuclease system, has made it possible to reconsider this challenge. For such purpose, a particular type of transposons referred to as miniature inverted-repeat transposable elements (MITEs) has shown a series of interesting characteristics for designing functional drivers. Here, recent insights into MITE elements and versatile RNA-guided CRISPR/Cas9 genome engineering system are given to understand how to deploy the potential of TEs for control of the host transcriptional activity.Fil: Vaschetto, Luis Maria Benjamin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Diversidad y Ecología Animal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto de Diversidad y Ecología Animal; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Cátedra de Diversidad Animal I; Argentin

Problem-solving therapy rather than treatment as usual for adults after self-harm: a pragmatic, feasibility, randomised controlled trial (the MIDSHIPS trial)

Background: Non-fatal self-harm is one of the commonest reasons for adults’ emergency hospital attendance. Although strongly associated with fatal and non-fatal repetition, there is weak evidence about effective interventions—and no clear NICE guidance or clinical consensus concerning aftercare. We examined the practicability of a definitive trial to evaluate problem-solving therapy (PST) to reduce repetition of self-harm; MIDSHIPS is a single-centre, parallel-group, individually randomised controlled feasibility trial comparing treatment-as-usual (TAU) alone to TAU plus up to six sessions of brief problem-solving therapy (PST) with adults who had recently attended hospital because of self-harm. Objectives were to adapt the intervention for a UK setting, train therapists, recruit and randomise patients, deliver PST under supervision, and establish comparative outcomes, assessed blindly. Methods: We adapted the problem-solving intervention from an earlier trial and trained a mental-health nurse to deliver it. Adult patients attending the general hospital for self-harm were recruited while undergoing psychosocial assessment by the mental health team, and 62 were randomly allocated (32 TAU, 30 PST). The primary outcome assessed repeat hospital attendance due to further self-harm 6 months post-randomisation. Secondary outcomes included participant-reported outcomes and service use at 3 and 6 months post-randomisation. Results: The recruitment period had to be extended and 710 patients screened in order to establish a trial sample of the planned size (N = 62). A quarter of participants allocated to PST did not undertake the therapy offered; those who received PST attended a median of three sessions. Secondary outcomes were established for 49 (79%) participants at 6 months; all participants’ hospital records were retrieved. Repetition of self-harm leading to hospital presentation occurred in 19 of the 62 participants (30.6%, 95% CI 19.2%, 42.1%) within 6 months of randomisation. Promising differential rates of self-harm were observed with an event rate of 23.3% (95% CI 8.2%, 38.5%) in the PST arm; and 37.5% (95% CI 20.7%, 54.3%) in TAU. Economic findings were also encouraging, with a small QALY gain (0.0203) in the PST arm together with less reported use of the NHS in the PST arm (average £2120) than with TAU-only (£2878). Conclusions: The feasibility trial achieved its objectives despite considerable difficulties with recruitment—adapting the PST, training a therapist, recruiting patients who had recently self-harmed, delivering the therapy, and establishing primary and secondary outcomes. These data provide a robust platform for a definitive multicentre randomised controlled trial of brief problem-solving therapy after hospital attendance due to self-harm. Trial registration: Identification number and URL: ISRCTN54036115 http://www.isrctn.com/search?q=midships. Registered: 13 January 201

Understanding how education/support groups help lone mothers

<p>Abstract</p> <p>Background</p> <p>Lone-mother led families are at increased risk of psychosocial disadvantage, social isolation and mental health morbidity. Community-based programs are more accessible for families seeking assistance. We examine the experiences of eight lone mothers participating in a larger randomized controlled trial (RCT) of a community-based education/support group program using mixed methods.</p> <p>Methods</p> <p>A purposeful sample of eight mothers participating in the intervention arm of an RCT of community-based support/education groups was selected for the qualitative study. Individual interviews asked mothers about themselves and their relationships with their children before and after the group. Interviews were taped, transcribed and content analysis was used to code and interpret the data. Quantitative data collected in the RCT were used to describe these mothers.</p> <p>Results</p> <p>Mothers participating in the RCT and qualitative study experienced multiple difficulties, including financial and mood problems. These mothers reported that before participating in the group, they had shared experiences of social isolation, stigma, a sense of failure, poor relationships with their children and difficulties with financial management. After the group, mothers identified improved self-esteem, support from other mothers, improved parenting skills and improved communication with their children as outcomes of group participation.</p> <p>Conclusions</p> <p>The qualitative data revealed mothers' perceptions of specific areas that improved by participating in the group. The utility of complementary information provided by qualitative and quantitative methods in understanding program impact, as well as the need for broader assistance is noted.</p

Maladaptive behaviors are linked with inefficient sleep in individuals with developmental disabilities

The purpose of the current study was to assess the relations between nightly sleep patterns and the frequency of daily maladaptive behavior. Antecedent and consequential relations between sleep patterns and behavior were evaluated with time series analysis. Sleep efficiency and maladaptive behavior were determined for 20 female residents of an institutional care facility for adults with developmental disabilities. Daily maladaptive behavioral data and nightly sleep/awake logs were collected for 4 months for each participant. Efficient sleep patterns were significantly associated with lower frequencies of maladaptive behaviors. All lagged cross-correlations 8 days before and 8 days after an evening of sleep were significant. These findings suggested that inefficient sleep was associated with increased maladaptive behaviors and that the lagged associations reflected a chronic but not an acute linkage between sleep and behavior