11237 research outputs found
Sort by
Investigating the role of phosphodiesterases in myofibroblast transformation in Peyronie's disease
No full textIntroduction: Peyronie’s disease (PD) is characterised by a fibrous plaque that forms in the penile tunica albuginea (TA), leading to pain, penile deformity, and erectile dysfunction. There is currently no effective medical treatment available. The transformation of fibroblasts into myofibroblasts is a key event in the pathophysiology of PD, and previous work has shown that phosphodiesterase type 5 (PDE5) inhibitors can prevent this transformation in vitro and in vivo. This study aims to identify the molecular mechanism of the anti-myofibroblast action of PDE5 inhibitors.Materials and Methods: Primary fibroblasts were isolated from the TA of patients undergoing corrective surgery for PD. In-cell ELISA (ICE) assays were used to quantify expression of myofibroblast marker α-smooth muscle actin in response to TGF-β1. Concentration response curves of PDE5 inhibitors and activators/inhibitors of cGMP/cAMP pathway components were generated. Intracellular cGMP/cAMP concentrations were measured using cAMP/cGMP assays. RT-qPCR and ICE were used to investigate mRNA/protein expression.Results: PDE5 inhibitors (vardenafil, sildenafil and tadalafil), a nitric oxide (NO) donor, and soluble guanylyl cyclase (sGC) stimulators prevented TGF-β1-induced myofibroblast transformation, but natriuretic peptides and a protein kinase G (PKG) activator did not. Addition of a sGC inhibitor or a PKG inhibitor did not prevent the antifibrotic action of vardenafil. Forskolin and a cAMP analog abrogated myofibroblast transformation, whilst a combination of forskolin and vardenafil synergised. Addition of a protein kinase A (PKA) inhibitor prevented the antifibrotic action of vardenafil. No PDE5 inhibitors increased intracellular cGMP, but vardenafil and tadalafil significantly increased cAMP levels. RT-qPCR and ICE confirmed the expression of PDE1A, PDE1C, PDE4, PDE5A, PDE7B, and PDE8B. PDE1 inhibitor ITI-214 and PDE4 inhibitor roflumilast N-oxide inhibited myofibroblast transformation and significantly increased intracellular cAMP at a 10-1000-fold greater potency than PDE5 inhibitors.Discussion: Contrary to my initial hypothesis, these results suggest that PDE5 inhibitors, at pharmacological concentrations, prevent TGF-β1-induced transformation of myofibroblasts through the cAMP/PKA pathway, potentially via off-target inhibition of PDE1/PDE4. This is the first demonstration that PD fibroblasts express PDE1, PDE7 and PDE8, and that PDE1 and PDE4 inhibitors prevent myofibroblast transformation. This study suggests the development of PDE1/4 inhibitors for the treatment of acute PD.</p
Coaches’ experience of the importance, development and integration of decision-making and visual exploratory behaviour in an elite football academy setting
No full textEffective visual exploratory activity (VEA) and decision-making are integral to being an elite football player. Despite this, there is a lack of understanding regarding how these skills are coached and developed in a youth academy setting. Twelve male, football club youth academy coaches were interviewed to develop an understanding of their approach to coaching VEA and decision-making. Using a reflexive thematic analysis, the findings highlight that in order to maximise the impact of developing VEA and decision-making, coaches and players need to work together to create a shared understanding and common language using a combination of questions, phrases and video analysis. Integrating VEA and decision-making successfully in developmental sessions were viewed as most effective in opposed, chaotic training, which provides frequent opportunity for players to utilise problem solving skills (cf. develop conditional knowledge). Developing and delivering “chaotic” sessions was impacted by coach experience and development of the coach–player relationship.</p
Toll-like receptor stimulants in processed meats promote lipid accumulation in macrophages and atherosclerosis in Apoe−/− mice
No full textDietary intake of processed meat is a risk factor for cardiovascular disease. However, the effects of processed meats on lipid metabolism in macrophages, a key regulator of cardiovascular risk, have remained largely unexplored. Extracts of processed meats, but not their fresh non-processed equivalents, were found to promote a significant increase in macrophage lipid accumulation in vitro. Calibrated receptor-dependent reporter assays revealed that pro-inflammatory stimulants of Toll-like receptor (TLR)-2 and TLR4 were low or undetectable in fresh meats, but rose dramatically following chopping and storage at 4 °C. Lipid accumulation in response to processed meats correlated well with TLR-stimulant content, was significantly reduced in TLR4-deficient macrophages, and was absent in response to meats stored frozen to prevent bacterial growth. TLR-stimulation significantly increased the incorporation of 14C-acetate into cellular lipids, and induced lipid accumulation in the absence of exogenous lipoproteins, suggesting a key role for de novo lipid synthesis in this process. Aortic atherosclerosis was also significantly accelerated in Apoe−/− mice receiving a diet supplemented with TLR-stimulants at concentrations relevant to those measured in processed meats, compared to normal chow. The findings reveal novel mechanisms which may be of relevance to the observed connections between processed meat consumption, inflammatory markers and cardiovascular risk.</p
A scoping study of crime facilitated by the metaverse
No full textThe metaverse is an emerging convergence of technologies (e.g., virtual reality and blockchains) that enables users to experience mixed/extended realities for various legitimate purposes (e.g., gaming, tourism, manufacturing and education). Unfortunately, the crime and security implications of emerging technologies are often overlooked. To anticipate crimes that the metaverse might facilitate, we report the findings of a nominal group technique (NGT) study, which involved a state-of-the-art scoping review of the existing literature and elicitation exercises with two groups of experts (one a diverse group from the UK and Europe, the other representing international law enforcement) with a wide range of expertise. A total of 30 crime threats were identified in the literature or by participants. The elicitation exercises also explored how harmful, frequent, achievable and defeatable participants anticipated that the crimes identified would be. Ratings for these aspects were largely consistent across the two samples, with crimes of a sexual nature (e.g., child sexual abuse material), and crimes against the person (e.g., hate crime) being rated as presenting the highest future risks (i.e. being high harm and high frequency) and being the most difficult to address. The findings illuminate understanding of the most (and least) harmful and likely crime threats the metaverse could facilitate and consequently help stakeholders to prioritise which offences to focus on. In discussing how the crime threats might be addressed, we consider roles and responsibilities and how theory about the management of physical places might inform crime prevention in the metaverse(s).</p
Mobilising volunteers to deliver a school-based arts-in-nature practice to support children’s mental health and wellbeing: a modified e-Delphi Study with primary school staff
No full textArts-in-nature practice has been shown to have positive impacts on children’s mental health and wellbeing; however, introducing new innovations in schools can be challenging and requires involvement of staff in the process. The ‘Branching Out’ project explored how arts-in-nature practice can be scaled up to achieve greater reach in primary schools by mobilising community volunteers. We implemented an exploratory, multi-level mixed methods approach, including a modified e-Delphi study which was used to achieve consensus around a new delivery model of arts-in-nature practice in primary schools. Whilst a pilot study tested the implementation of the proposed model in one region, the e-Delphi study explored how the proposed Branching Out model, including the use of volunteers and various options for delivery, would be perceived more widely by primary school staff across different contexts. The survey incorporated implementation measures designed to determine the acceptability, appropriateness, and feasibility of the proposed model. Completion of two rounds of the e-Delphi study captured the views of 42 primary school staff members in total. The findings confirmed the acceptability of the arts-in-nature practice and the use of volunteers, suggested appropriate staff champions and groups of children who would benefit, and determined the preferred options for delivery in terms of feasibility. Overall, consensus was reached regarding the proposed model of arts-in-nature practice in primary schools with high levels of agreement regarding its acceptability, appropriateness, and feasibility. The e-Delphi study provided valuable perspectives of primary school staff that led to the refinement of the Branching Out model for mobilising volunteers to deliver arts-in-nature practice to promote children’s mental health. Delphi studies have the potential to enable expert input into policy and practice and provide an opportunity for teachers to have a voice in the delivery and development of school-based interventions
Exploration behavior differs between Darwin’s finch species and predicts territory defense and hatching success
No full textDarwin’s finch species in the Galápagos Islands are famously distinguished by their morphology but less attention has been given to behavioral differences between species. In this study, we compared behavior between four Darwin’s finch species on Floreana Island: small ground finch (Geospiza fuliginosa), medium ground finch (G. fortis), small tree finch (Camarhynchus parvulus), and medium tree finch (C. pauper). After capturing birds using mist-nets, we measured three behavioral traits: (1) boldness during human handling, (2) exploration in a novel environment, and (3) aggressiveness towards their mirror image. First, we found that ground finches were bolder and more exploratory than tree finches, consistent with their distinct ecological niches on Floreana Island and with the theoretical prediction that diet generalists should be less wary of novelty. Second, we tested the ecological validity of these behavioral variables at the individual level by relating them to territory defense behavior and breeding success. We found that males that were more exploratory in the novel environment also reacted more aggressively to a simulated territory intruder and showed lower offspring hatching success during the breeding season. Hence, our findings support previous work showing behavioral differences between Darwin’s finch species and also suggest pathways by which behavioral differences among individuals might influence fitness. Significance statementClosely-related species that overlap in their geographical range may differ in their morphology and/or behavior, allowing them to occupy different ecological niches. In this study, we explored behavioral differences between four Darwin’s finch species on Floreana Island in the Galápagos Archipelago. We found clear interspecies differences in behavior, with the ground finches struggling more often during handling (boldness) and visiting more sectors in a novel environment (exploration) compared to the tree finches. After birds were released, we continued to observe a subset of male finches in the wild. An individual’s exploration behavior significantly predicted both its aggressive response to a territory intruder (simulated using song playback) and offspring hatching success during the breeding season. This suggests that individual differences in exploration behavior can potentially be used as a proxy for territorial behavior in the wild and may also predict fitness outcomes.</p
Where Past Meets the Future of Medieval Rhodes: New Mortar Solutions for Conservation of the Buildings
No full textThe interaction between the historical context of the medieval town of Rhodes and contemporary demands shapes the requirements for building strategies and materials, that could support sustainable solutions, particularly those applicable to conservation mortars.</p
Abstract Foundations of a Conceptual Architecture: Superstudio's Continuous Monument and the Theories of Paul Klee
No full textArticle on the relationship between Paul Klee’s theories and the pictorial activity of Adolfo Natalini, Superstudio’s founder, and Klee’s influence on Superstudio’s work, in particular the Continuous Monument (1969).</p
Nineteenth-Century Literature in Transition: The 1830s
No full textThis instalment in the Nineteenth-Century Literature in Transition series concerns a decade that was as technologically transitional as it was eventful on a global scale. It collects work from a group of internationally renowned scholars across disciplinary boundaries in order to engage with the wide array of cultural developments that defined the 1830s. Often overlooked as a boundary between the Romantic and Victorian periods, this decade was, the book proposes, the central pivot of the nineteenth century. Far from a time of peaceful reform, it was marked by violent colonial expansion, political resistance, and revolutionary technologies such as the photograph, the expansion of steam power, and the railway that changed the world irreversibly. Contributors explore a flurry of cultural forms to take the pulse of the decade, from Silver Fork fiction to lithography, from working-class periodicals to photographs, and from urban sketches to magazine fiction.</p
The compass project intervention programme: the application of moral theory in different youth contexts
No full textPurpose: The study aims to introduce The Compass Project (TCP), designed to determine whether strengthening morality and practicing emotion management can reduce youth antisocial attitudes and behaviours and increase prosocial attitudes and behaviours.The programme activities are informed by the existing evidence base and incorporate theoretical explanations of the mechanisms that link psychological moral and emotional traits and behaviour. Design/methodology/approach: This paper will offer a description of the programme design and content, TCP 2022 pilot study and crucially, discuss the utility of delivering programmes like TCP in wider settings (schools, youth offending teams and other youth organisations). TCP is currently being delivered in UK schools as a multi-site, longitudinal, RCT design. Findings: Participant feedback from TCP 2022 pilot study is used to illustrate the potential impact of TCP for young people in future. The authors identify five challenges faced by researchers conducting youth intervention studies: access, recruitment, continued attendance, nature of participation (enthusiasm, engagement and task-focus) and full participant completion of data measures. Practical implications: This pioneering study offers a novel methodology to increase law-abiding moral attitudes and behaviours in young people. This paper adopts a forward-thinking and scientific approach to identify practical solutions to key challenges faced when delivering youth interventions and is relevant for youth practitioners and academics worldwide. Social implications: TCP seeks to achieve improved youth attitudinal outcomes (such as law-aligned morality, empathy for others, measured decision-making and consideration of the consequences of action) and improved youth behavioural outcomes (such as improved quality of relationships with others, increased helping and prosocial behaviours, reduced antisocial behaviour and delinquency and reduced contact with criminal justice system-related organisations). Originality/value: To the best of the authors’ knowledge, an evidence-based morality strengthening and emotion programme of this kind, closely aligned with a moral theory of rule-breaking, has not been developed before.</p
Data sources:
Access Repository Dashboard
Do you manage Open Research Online? Become a CORE Member to access insider analytics, issue reports and manage access to outputs from your repository in the CORE Repository Dashboard! 👇