Prenatal muscle development in a mouse model for the secondary dystroglycanopathies

The defective glycosylation of α-dystroglycan is associated with a group of muscular dystrophies that are collectively referred to as the secondary dystroglycanopathies. Mutations in the gene encoding fukutin-related protein (FKRP) are one of the most common causes of secondary dystroglycanopathy in the UK and are associated with a wide spectrum of disease. Whilst central nervous system involvement has a prenatal onset, no studies have addressed prenatal muscle development in any of the mouse models for this group of diseases. In view of the pivotal role of α-dystroglycan in early basement membrane formation, we sought to determine if the muscle formation was altered in a mouse model of FKRP-related dystrophy

Transgenic Rescue of the LARGEmyd Mouse: A LARGE Therapeutic Window?

LARGE is a glycosyltransferase involved in glycosylation of α-dystroglycan (α-DG). Absence of this protein in the LARGEmyd mouse results in α-DG hypoglycosylation, and is associated with central nervous system abnormalities and progressive muscular dystrophy. Up-regulation of LARGE has previously been proposed as a therapy for the secondary dystroglycanopathies: overexpression in cells compensates for defects in multiple dystroglycanopathy genes. Counterintuitively, LARGE overexpression in an FKRP-deficient mouse exacerbates pathology, suggesting that modulation of α-DG glycosylation requires further investigation. Here we demonstrate that transgenic expression of human LARGE (LARGE-LV5) in the LARGEmyd mouse restores α-DG glycosylation (with marked hyperglycosylation in muscle) and that this corrects both the muscle pathology and brain architecture. By quantitative analyses of LARGE transcripts we also here show that levels of transgenic and endogenous LARGE in the brains of transgenic animals are comparable, but that the transgene is markedly overexpressed in heart and particularly skeletal muscle (20–100 fold over endogenous). Our data suggest LARGE overexpression may only be deleterious under a forced regenerative context, such as that resulting from a reduction in FKRP: in the absence of such a defect we show that systemic expression of LARGE can indeed act therapeutically, and that even dramatic LARGE overexpression is well-tolerated in heart and skeletal muscle. Moreover, correction of LARGEmyd brain pathology with only moderate, near-physiological LARGE expression suggests a generous therapeutic window

Susceptibility of Aedes albopictus and Culex quinquefasciatus to Japanese encephalitis virus; 35710580

Background: Japanese encephalitis virus (JEV) is the principal cause of mosquito-borne encephalitis in human populations within Asia. If introduced into new geographic areas, it could have further implications for public and animal health. However, potential mosquito vectors for virus transmission have not been fully investigated. The Asian tiger mosquito, Aedes albopictus, has emerged in Europe and is now expanding its geographical range into more northerly latitudes. Culex quinquefasciatus, although absent from Europe, has been detected in Turkey, a country with territory in Europe, and could act as a vector for JEV in other regions. To assess the risk of these invasive species acting as vectors for JEV and therefore potentially contributing to its geographical expansion, we have investigated the vector competence of Ae. albopictus and Cx. quinquefasciatus. Methods: Two colonised lines of Ae. albopictus (Italy and Spain) and a line of Cx. quinquefasciatus (Tanzania) were compared for susceptibility to infection by oral feeding with JEV strain SA-14, genotype III at 106 PFU/ml and maintained at 25 °C. Specimens were processed at 7 and 14 days post-inoculation (dpi). Rates of infection, dissemination and transmission were assessed through detection of viral RNA by real-time polymerase chain reaction (RT-PCR) in mosquito body, legs and saliva, respectively, at each time point. Where possible, infection and dissemination were confirmed by immunohistochemical (IHC) detection of the JEV envelope protein. Results: Aedes albopictus from Italy showed no susceptibility to infection with JEV strain SA-14. Conversely, Ae. albopictus colonised in Spain was susceptible and 100% of infected mosquitoes that were subjected to saliva screening expressed viral RNA at 14 dpi. Culex quinquefasciatus was highly susceptible to infection as early as 7 dpi and 50% of infected mosquitoes that were subjected to saliva screening expressed viral RNA at 14 dpi. Infection and dissemination were confirmed in Cx. quinquefasciatus by IHC detection of JEV envelope protein in both the mid-gut and salivary glands. Conclusions: Aedes albopictus from two different locations in Europe range from being susceptible to JEV and capable of transmission through to being resistant. Culex quinquefasciatus also appears highly susceptible; therefore, both species could potentially act as vectors for JEV and facilitate the emergence of JEV into new regions. Graphical Abstract: Figure not available: see fulltext.] © 2022, The Author(s)

Monsters: interdisciplinary explorations in monstrosity

There is a continued fascination with all things monster. This is partly due to the popular reception of Mary Shelley’s Monster, termed a “new species” by its overreaching but admiringly determined maker Victor Frankenstein in the eponymous novel first published in 1818. The enduring impact of Shelley’s novel, which spans a plethora of subjects and genres in imagery and themes, raises questions of origin and identity, death, birth and family relationships as well as the contradictory qualities of the monster. Monsters serve as metaphors for anxieties of aberration and innovation. Stephen Asma (2009) notes that monsters represent evil or moral transgression and each epoch, to speak with Michel Foucault, evidences a “particular type of monster” (2003, 66). Academic debates tend to explore how social and cultural threats come to be embodied in the figure of a monster and their actions literalize our deepest fears. Monsters in contemporary culture, however, have become are more humane than ever before. Monsters are strong, resilient, creative and sly creatures. Through their playful and invigorating energy they can be seen to disrupt and unsettle. They still cater to the appetite for horror, but they also encourage us to feel empathy. The encounter with a monster can enable us to stop, wonder and change our attitudes towards technology and our body and each other. This commentary article considers the use of the concepts of ‘monsters’ or ‘monstrosity’ in literature, contemporary research, culture and teaching contexts at the intersection of the Humanities and the Social Sciences

Systematic mechanical assessment of consolidants for canvas reinforcement under controlled environment

In conservation, adhesives are commonly used for the consolidation of canvases, yet their impact upon the canvas longevity has raised some concerns amongst conservators. As such, this study presents a testing protocol developed to assess the performance of commonly-used adhesives (natural animal glue and synthetic Beva® 371) and a newly developed nanocellulose consolidant, nanofibrillated nanocellulose (CNF). This includes their effect on the visual appearance, consolidation, and response of the mechanical properties of the treated canvases to programmed changes in relative humidity (RH). Scanning electron microscopy (SEM) images of animal glue- and Beva® 371-treated canvases revealed the presence of adhesive and consolidant on and in-between cotton fibres. The consolidants form bridges linking and connecting the cotton fibres and holding them together, whereas the CNF treatment, formed a visible continuous and dense surface coating. None of the treatments induced any discernible colour change. Controlled environment mechanical testing was performed in two ways: by applying a linearly increasing static force at fixed RH (Young’s modulus) and by applying a dynamic force together with a programmed RH cycling between 20 and 80% (RH dependent viscoelastic properties). CNF gave a higher value of Young’s modulus than either of the two commonly-used materials. Measurements at different values of RH (20 and 80%) demonstrated for all the treated canvases that at the lower value (RH 20%) Young’s modulus values were higher than at the higher value (RH 80%). Besides, the dynamic mode showed that the rate of response in all cases was rapid and reversible and that the nanofibrillated cellulose treated sample showed the highest variation in storage (or elastic) modulus measured at the end of RH plateaux (20 and 80% RH). Thus CNF appears to be a promising material given its higher mechanical performance. The protocol developed in this study has enabled us to examine and compare candidate materials for the consolidation of canvases systematically, using testing parameters that remained relevant to the field of canvas conservation

Productive resistance within the public sector: exploring organisational culture

The article examines how South Korean civil servants responded to the introduction of pay for performance. Drawing upon 31 in-depth interviews with career civil servants, it identifies what became known as 1/n, a form of ‘discreet resistance’ that emerged and evolved. The analytical framework allows productive resistance to be seen as ebbing and flowing during organisational change that sees institutionalisation, deinstitutionalisation and re-institutionalisation. In understanding the cultural context of organisational resistance the contribution is three-fold. First, a nuanced definition and understanding of productive resistance. Second, it argues that productive resistance must be seen as part of a process that does not simply reflect ‘offer and counter-offer’ within the change management process. Thirdly, it identifies differences within groups and sub-cultures concerning commitment towards resistance and how these fissures contribute towards change as new interpretive schemes and justifications are presented in light of policy reformulations