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Alterations in cardiac function correlate with a disruption in fatty acid metabolism in a mouse model of SMA
No full textSpinal Muscular Atrophy is an autosomal dominant disease caused by mutations and deletions within the SMN1 gene, with predominantly childhood onset. Although primarily a motor neuron disease, defects in non-neuronal tissues are described in both patients and mouse models. Here, we have undertaken a detailed study of the heart in the Smn2B/- mouse models of SMA, and reveal a thinning of the ventriclar walls as previously described in more severe mouse models of SMA. However most structural changes are resolved by accounting for the smaller body size of the SMA mouse, as was also confirmed in the SMN∆7 model. Echocardiography revealed increased systolic function, which was particularly pronounced in subsets of mice and an increase in global longitudinal strain, collectively indicative of increased cardiac stress in the Smn2B/- mouse model. We have used TMT proteomics to perform a longitudinal study of the proteome of the hearts of Smn2B/- mice and reveal a progressive dysregulation of LXR/RXR signalling which is a regulator of lipid metabolism. We further show consistent perturbations in lipid metabolism in the Smn2B/-, Smn-/-;SMN2;SmnΔ7and SmnΔ7/Δ7;SMN2 mouse models of SMA on the day of birth. This work indicates that although structural changes in the heart can be overstated by failing to account for body size, there are functional defects which could predispose the heart to subsequent failure. We identify a common molecular signature across mouse models pointing to a dysregulation in lipid metabolism, and suggest that manipulation of LXR/RXR signalling offers an opportunity to impact upon these pathways.</p
ZYG-12/Hook's dual role as a dynein adaptor for early endosomes and nuclei is regulated by alternative splicing of its cargo binding domain:Molecular Biology of the Cell
No full textThe microtubule motor cytoplasmic dynein-1 transports and positions various organelles, but the molecular basis of this functional diversity is not fully understood. Cargo adaptors of the Hook protein family recruit dynein to early endosomes (EE) in fungi and human cells by forming the FTS?Hook?FHIP (FHF) complex. By contrast, the C. elegans Hook homolog ZYG-12 recruits dynein to the nuclear envelope (NE) in the meiotic gonad and mitotic early embryo by forming a Linker of Nucleoskeleton and Cytoskeleton (LINC) complex. Here, we demonstrate that ZYG-12 recruits dynein to EE in epithelia. We identify and functionally characterize the homologs of FTS (UBC-19) and FHIP (FHIP-1) that constitute the C. elegans FHF complex, validate the predicted FHIP-1?RAB-5 binding interface in vivo, and show that ZYG-12 forms FHF via a conserved segment that precedes, and is distinct from, its C-terminal NE targeting domain. Finally, we show that C-terminal ZYG-12 splice isoforms differ in their ability to target to the NE and EE. We conclude that the C. elegans Hook adaptor evolved to recruit dynein to two distinct organelles, and that cargo specificity of ZYG-12 is regulated by alternative splicing
Phylogenomics shed light on the complex evolutionary history of a gymnosperm genus showing East Asian–Tethyan disjunction
No full textWhen and how disjunct distributions of biological taxa arose has long attracted interest in biogeography, yet the East Asian–Tethyan disjunction is understudied. Cupressus (Cupressaceae) shows this disjunction, with 10 species in East Asia and three in the Mediterranean region. Here we used target-capture sequencing and obtained 1991 single-copy nuclear genes, plus complete plastomes, to infer the evolutionary history of Cupressus. Our phylogenomic reconstruction resolved four well supported clades in Cupressus, but revealed significant phylogenetic conflicts, with inter-lineage gene flow, incomplete lineage sorting and gene tree estimation error all making important contributions. The Chengiana clade most likely originated by hybridization between the ancestors of the Himalayan–Hengduan Mountains and subtropical Asia clades, whereas orogenic and climatic changes may have facilitated gene flow within the Himalayan–Hengduan Mountains clade. Molecular dating suggested that the most recent common ancestor of Cupressus appeared in East Asia around the middle Eocene period and then became continuously distributed across Eurasia. The East Asian–Tethyan disjunction arose when the Mediterranean and Himalayan–Hengduan Mountains clades diverged, likely to have been driven by Eocene/Oligocene declines in global temperature, then reinforced by the ecogeographic barrier created by the uplift of the Qinghai–Tibet Plateau. Niche shifts in the common ancestor of the Mediterranean clade, and signatures of selection in genes for drought and salt tolerance, probably indicate adaptation of this clade to local conditions. Overall, our study suggested that in-depth phylogenomic analyses are powerful tools in deciphering the complex evolutionary history of the origin of East Asian–Tethyan disjunction of organisms, especially gymnosperms.</p
Local knowledges and the right to participate in science
Get PDFI discuss the right to participate in science, which is part of the UN Declaration of Human Rights (1948) and the International Covenant on Economic Social and Cultural Rights (1966). Building on my previous work on this right as an ‘epistemic-cultural’ right, in this paper my goal is to clarify how fulfilling this right requires engaging with varieties of local knowledges that are too often severed in scientific narratives. I tease out three main varieties of local knowledges and highlight their distinctive features and their intersectionalities. In the second part of the paper, I argue that a more careful appreciation of varieties of local knowledges is not only key for the fulfilment of the right to participate in science but also for other human rights. I focus my attention here selectively on the right to food, and right to clean water. I conclude by highlighting the implications of this discussion for ongoing legal debates on rights of nature
Raman active diyne-girder conformationally constrained p53 stapled peptides bind to MDM2 for visualisation without fluorophores
Get PDFPeptide stapling is an effective strategy to stabilise α-helical peptides, enhancing their bioactive conformation and improving physiochemical properties. In this study, we apply our novel diyne-girder stapling approach to the MDM2/MDMX α-helical binding region of the p53 transactivation domain. By incorporation of an unnatural amino acid to create an optimal i, i + 7 bridge length, we developed a highly α-helical stapled peptide, 4, confirmed via circular dichroism. This diyne-girder-stapled peptide demonstrated enhanced helicity and nanomolar binding affinity for MDM2, as assessed by fluorescence polarisation. Crucially, peptide 4 exhibited strong selectivity for MDM2, with approximately 100-fold reduced affinity for MDMX. Molecular modeling and docking studies suggested that this selectivity arose from diminished hydrophobic interactions at the MDMX binding site, driven by the diyne-girder's constrained geometry. The use of the diyne-girder, a unique feature amongst stapled peptide analogues, for cellular visualisation using Raman spectroscopy in the “cell-silent” region was explored. This capability potentially offers a novel method for tracking stapled peptides in biological systems without the need for large fluorophores. Overall, peptide 4 represents a promising tool for probing MDM2 activity and a valuable addition to the arsenal of peptide-based therapeutic strategies
Revealing the synergistic effect in the BDD-based quadruple coupling system via active radical and non-radical species for efficient removal of refractory organic contaminant
Get PDFBoron-doped diamond (BDD)-based advanced oxidation processes featured exceptional advantages in treating refractory organic contaminants. Herein, we reported, for the first time, the BDD-based quadruple coupling system, namely (+)BDD|PMS + CoAl2O4+Air|GF(−), by fully integrating the advantages of electrochemical oxidation, peroxymonosulfate (PMS), CoAl2O4 and electro-Fenton-like process, to degrade tetracycline (TC) via active radicals (i.e., O2∙−, SO4∙−, ∙OH) and non-radical singlet oxygen (1O2). In the quadruple system, CoAl2O4 particles could be polarized into suspended particle electrodes, promoting PMS activation to form active radicals by homo- and heterogeneous pathways and expanding the reaction regions to a broad spatial range; meanwhile, aeration is the key to the electro-Fenton-like process and an indispensable source of 1O2. Interestingly, high concentrations of 1O2 existed both on the BDD surface and in the bulk solution whereas other active species only existed on the former, indicating the crucial role of 1O2 in the TC removal. Leveraging the synergistic effect, the quasi-first-order kinetic constant of the coupling system for TC removal was 8 times that of the single EO system at only the cost of one-seventh of its electric energy consumption. Finally, the proposed coupling system exhibited long-term stability and practical application potential.</p
Testing the interrelationship between area deprivation and ethnic disparities in sentencing
Get PDFIn the examination of sentencing disparities, hypotheses related to social class have been relatively overlooked compared to explanations centered on offenders' ethnicity. This oversight is regrettable as both factors often intertwine. In this study, we investigate the mediating and moderating effects between offenders' residential area deprivation and their ethnic background using administrative data encompassing all offences processed through the England and Wales Crown Court. Our findings reveal the following: (i) substantial ethnic disparities among drug offenders, but mostly non-existent across other offence categories; (ii) area deprivation does not explain away the observed ethnic disparities, but pronounced area disparities are found for breach and assault offenses, wherein offenders living in deprived areas are penalized compared to their more affluent counterparts; and (iii) ethnicity and area deprivation interact, but only for breach offenses.</p
The impact of the ‘accelerated childhood’ culture in UK's ECEC:Practitioners’ and policy makers’ views during a professional development course
Get PDFSlow Pedagogy has unhurriedly been making its way into early years practice. This article examines the views of early years practitioners and policy makers (N = 80) on slow pedagogical practice, during a professional development course. The participants were asked two open-ended questions: ‘Are children “hurried” today? If so in what ways?’ and ‘What does “unhurried child” mean to you?’. Thematic analysis was used to code the participants' responses. The findings indicated that early years practitioners and policy makers identified different ways in which children are hurried in their lives today, including ECEC. Through their reflections on what ‘unhurried child’ means, the findings indicated that early years practitioners and policy makers valued the benefits of ‘unhurried’ practice.</p
Co-creating cultural narratives for sustainable rural development:a transdisciplinary learning framework for guiding place-based social-ecological research
Get PDFPlace-based social-ecological research is crucial for understanding local sustainability challenges. However, lack of transferability of insights to other locations and to larger scales remains challenging. In this paper, we present a novel transdisciplinary learning framework that links notions of cultural heritage, landscape, and social-ecological systems thinking to support sustainable rural development. Continuous dialogue, learning, and collaboration among communities and stakeholders, including researchers, take centre stage in this framework. We outline the four steps of the framework, conceptually integrating and operationalising how dialogue, learning, and collaboration can take place in each step. We tested the framework in the CULTIVATE project (https://www.cultivate-project.net), which explored the role of cultural heritage narratives in supporting sustainable rural development in four European UNESCO Biosphere Reserves. The framework successfully guided our research and comparative cross-case analysis, thereby contributing to aggregate learnings from place-based social-ecological research to develop knowledge at the national or global scale.</p
A qualitative exploration of change processes relevant to compassion-focused therapy that occurs when people view both soothing and non-soothing images
Get PDFObjective: Using soothing imagery within psychotherapy may support people to undertake positive visualisation exercises. However, little is known about what processes happen when people view images they find to be soothing or non-soothing. Design: Exploratory qualitative methods were used. Method: Responses from 644 participants who had written about images they found to be soothing or non-soothing were analysed using thematic analysis. Results: Two key themes were developed that related to the importance of the image content (such as it being a natural scene or artificial) and the internal cognitive and psychological processes that it triggered within participants as being key drivers for an image being perceived as soothing or non-soothing. This included recall of positive autobiographical memories and liking the image content. Conversely, negative autobiographical memories and disliking image content were associated when people viewed images they considered to be non-soothing. Conclusions: Experiences of feeling soothed when viewing an image appear to be maintained by imagining positive sensory experiences that were associated with the image or linking the image to positive experiences from the participant's autobiographical memory. This has implications for the delivery of therapy using pre-existing image sets and suggests there is a need to find out what images are most suited for people accessing services.</p
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