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During animal development, organs grow to a fixed size and shape. Organ development typically begins with a rapid growth phase followed by a gradual decline in growth rate as the organ matures 1 , but the regulation of either stage of growth remains unclear. The Wnt/Wingless (Wg) proteins are critical for patterning most animal organs, have diverse effects on development and have been proposed to promote organ growth 2 . Here we report that contrary to this view, Wg activity actually constrains wing growth during Drosophila melanogaster wing development. In addition, we demonstrate that Wg is required for wing cell survival, particularly during the rapid growth phase of wing development. We propose that the cell-survival- and growth-constraining activities of Wg function to sculpt and delimit final wing size as part of its overall patterning programme.

AbstractObjectiveTo establish the effect of statins on muscle symptoms in people who had previously reported muscle symptoms when taking statins.DesignSeries of randomised, placebo controlled n-of-1 trials.SettingPrimary care across 50 sites in the United Kingdom, December 2016 to April 2018.Participants200 participants who had recently stopped or were considering stopping treatment with statins because of muscle symptoms.InterventionsParticipants were randomised to a sequence of six double blinded treatment periods (two months each) of atorvastatin 20 mg daily or placebo.Main outcome measuresAt the end of each treatment period, participants rated their muscle symptoms on a visual analogue scale (0-10). The primary analysis compared symptom scores in the statin and placebo periods.Results151 participants provided symptoms scores for at least one statin period and one placebo period and were included in the primary analysis. Overall, no difference in muscle symptom scores was found between the statin and placebo periods (mean difference statin minus placebo −0.11, 95% confidence interval −0.36 to 0.14; P=0.40)). Withdrawals because of intolerable muscle symptoms were 18 participants (9%) during a statin period and 13 (7%) during a placebo period. Two thirds of those completing the trial reported restarting long term treatment with statins.ConclusionsNo overall effect of atorvastatin 20 mg on muscle symptoms compared with placebo was found in participants who had previously reported severe muscle symptoms when taking statins. Most people completing the trial intended to restart treatment with statins. N-of-1 trials can assess drug effects at the group level and guide individual treatment.Trial registrationISRCTN30952488, EUDRACT 2016-000141-31, NCT02781064.

Kenngoor (Phascogale calura) persist in < 1% of their original distribution, occupying highly fragmented remnant habitat in south-west Western Australia, with very little known of the genetic diversity of the remaining wild populations. Recently, the species has been translocated to managed reserves to improve its conservation. Understanding genetic structure and patterns of genetic diversity is crucial to inform conservation translocations for species recovery. This study aims to (1) assess genetic structure and genetic diversity across remaining wild locations, (2) assess long-term genetic outcomes of a mixed-source wild-to-wild translocation, and (3) estimate global effective population size. We genotyped 209 samples from 13 locations of fragmented remnant habitat using reduced representation sequencing. An isolation by distance model best explained genetic structure across the survey areas, with evidence of fine scale divergence of two northern locations. Allelic richness and autosomal heterozygosity measures indicated that diversity is spread uniformly across locations, and no locations showed signs of inbreeding or strong genetic drift. The mixed-source translocation has retained the diversity of the wider species ten years post-translocation. Overall, our results suggest that connectivity between survey areas has largely been maintained and that no location has substantially lower genetic diversity, despite the highly fragmented nature of remnant kenngoor habitat. Future translocations should aim to represent a mixture of genetically divergent locations to maintain the diversity present at the species level. Ongoing conservation management will be required to ensure the long-term viability of the species in this fragmented landscape.

Changed fire regimes have led to declines of fire-regime-adapted species and loss of biodiversity globally. Fire affects population processes of growth, reproduction, and dispersal in different ways, but there is little guidance about the best fire regime(s) to maintain species population processes in fire-prone ecosystems. We use a process-based approach to determine the best range of fire intervals for keystone plant species in a highly modified Mediterranean ecosystem in southwestern Australia where current fire regimes vary. In highly fragmented areas, fires are few due to limited ignitions and active suppression of wildfire on private land, while in highly connected protected areas fires are frequent and extensive. Using matrix population models, we predict population growth of seven Banksia species under different environmental conditions and patch connectivity, and evaluate the sensitivity of species survival to different fire management strategies and burning intervals. We discover that contrasting, complementary patterns of species life-histories with time since fire result in no single best fire regime. All strategies result in the local patch extinction of at least one species. A small number of burning strategies secure complementary species sets depending on connectivity and post-fire growing conditions. A strategy of no fire always leads to fewer species persisting than prescribed fire or random wildfire, while too-frequent or too-rare burning regimes lead to the possible local extinction of all species. In low landscape connectivity, we find a smaller range of suitable fire intervals, and strategies of prescribed or random burning result in a lower number of species with positive growth rates after 100 years on average compared with burning high connectivity patches. Prescribed fire may reduce or increase extinction risk when applied in combination with wildfire depending on patch connectivity. Poor growing conditions result in a significantly reduced number of species exhibiting positive growth rates after 100 years of management. By exploring the consequences of managing fire, we are able to identify which species are likely to disappear under a given fire regime. Identifying the appropriate complementarity of fire intervals, and their species-specific as well as community-level consequences, is crucial to reduce local extinctions of species in fragmented fire-prone landscapes.

Background Patient and Public Involvement (PPI) in research is a growing field of work, incorporating experiential knowledge within research processes. Co-production is a more recent PPI approach that emphasises the importance of power-sharing to promote inclusive research practices, valuing and respecting knowledge from different sources, and relationship building. Applying co-production principles in research trials can be difficult, and there are few detailed worked examples or toolkits. This paper explores the successes and challenges encountered by one research team. Methods Our paper is written by a team of 21 people working on PARTNERS2, led by a smaller co-ordinating group. Using a co-operative style inquiry, the authors have reflected on and written about their experiences; analysis of the resulting 15 accounts provided examples of how PPI and co-production were delivered in practice. Results We reveal varied and complicated experiences as we developed our collaborative approach across the entire research programme. Four main themes emerge from reflective accounts which describe aspects of this process: (1) recognising the importance of ‘emotional work’; (2) developing safe spaces to create and share knowledge; (3) some challenges of using our personal identities in research work; and (4) acknowledging power-sharing within the research hierarchy. We also found continual relationship building, how different forms of expertise were valued, and stigma were central to shaping what work was possible together. Other important practices were transparency, particularly over decision making, and clear communication. Conclusions Our work provides one example of the ‘messy’ nature of collaborative research in practice. The learning we surface was contextual, generated within a large-scale research programme, but applicable to other studies. We found for success there needs to be an acknowledgement of the importance of emotional work, creating safe spaces to co-produce, transparency in decision making and reflection on the difficulties of using personal identities in research work including for service user researchers. These elements are more important than existing guidelines suggest. Implementation of actions to support emotional work, will require changes within individual teams as well as institutions. Introducing reflective practice in teams may be helpful in identifying further improvements to inclusive research practice.

AimsA robust immunohistochemistry (IHC) assay was developed to detect lymphocyte-activation gene 3 (LAG-3) expression by immune cells (ICs) in tumour tissues. LAG-3 is an immuno-oncology target with demonstrable clinical benefit, and there is a need for a standardised, well-characterised assay to measure its expression. This study aims to describe LAG-3 scoring criteria and present the specificity, sensitivity, analytical precision and reproducibility of this assay.MethodsThe specificity of the assay was investigated by antigen competition and with LAG3 knockout cell lines. A melanin pigment removal procedure was implemented to prevent melanin interference in IHC interpretation. Formalin-fixed paraffin-embedded (FFPE) human melanoma samples with a range of LAG-3 expression levels were used to assess the sensitivity and analytical precision of the assay with a ≥1% cut-off to determine LAG-3 positivity. Interobserver and intraobserver reproducibility were evaluated with 60 samples in intralaboratory studies and 70 samples in interlaboratory studies.ResultsThe LAG-3 IHC method demonstrated performance suitable for analysis of LAG-3 IC expression in clinical melanoma samples. The pretreatment step effectively removed melanin pigment that could interfere with interpretation. LAG-3 antigen competition and analysis of LAG3 knockout cell lines indicated that the 17B4 antibody clone binds specifically to LAG-3. The intrarun repeatability, interday, interinstrument, interoperator and inter-reagent lot reproducibility demonstrated a high scoring concordance (>95%). The interobserver and intraobserver reproducibility and overall interlaboratory and intralaboratory reproducibility also showed high scoring concordance (>90%).ConclusionsWe have demonstrated that the assay reliably assesses LAG-3 expression in FFPE human melanoma samples by IHC.

Educators from Europe, Latin America, and the United States convened to explore issues inherent in democratic citizenship. Media literacy, a central component of democratic citizenship, was studied in depth. Data from the camp were examined for evidence of the participants' understandings of media literacy and how it might be taught. Results revealed that the camp participants developed a deeper understanding of media literacy, the importance of its teaching, and ways to teach it.