Targeting Relevant HDACs to Support the Survival of Cone Photoreceptors in Inherited Retinal Diseases: Identification of a Potent Pharmacological Tool with In Vitro and In Vivo Efficacy.

Inherited retinal diseases, which include retinitis pigmentosa, are a family of genetic disorders characterized by gradual rod-cone degeneration and vision loss, without effective pharmacological treatments. Experimental approaches aim to delay disease progression, supporting cones' survival, crucial for human vision. Histone deacetylases (HDACs) mediate the activation of epigenetic and nonepigenetic pathways that modulate cone degeneration in RP mouse models. We developed new HDAC inhibitors (5a-p), typified by a tetrahydro-γ-carboline scaffold, characterized by high HDAC6 inhibition potency with balanced physicochemical properties for in vivo studies. Compound 5d (repistat, IC50 HDAC6 = 6.32 nM) increased the levels of acetylated α-tubulin compared to histone H3 in ARPE-19 and 661W cells. 5d promoted vision rescue in the atp6v0e1-/- zebrafish model of photoreceptor dysfunction. A single intravitreal injection of 5d in the rd10 mouse model of RP supported morphological and functional preservation of cone cells and maintenance of the retinal pigment epithelium array.

Exploring farmer and advisor lameness management behaviors using the COM-B model of behavior change.

Introduction: This paper applies the COM-B framework to farmer and farm advisor understandings and responses to lameness in sheep, beef, and dairy systems. It reflects on how farmers' and advisors' capability, opportunity, and motivation (COM-B) influence lameness management practices in these farming systems, and considers the interaction between these three factors, and stakeholders' behavior. Methods: Interviews with 29 farmers and 21 farm advisors in the north of England were conducted. Thematic analysis was undertaken with results categorized in relation to the COM-B framework focusing on barriers and enablers of lameness management. Use of the COM-B model provides a useful means of understanding the underlying behavioral mechanisms that contribute toward the persistence of lameness. This includes the complexities and interactions which hamper implementation of lameness management best practice. Results and discussion: The findings highlight three key areas to address with interventions to improve lameness management on farm: (1) removing physical and social barriers for lameness management; (2) improving psychological capability and motivation for lameness management; and (3) facilitating relationships and developing communication between farmers and advisors. In particular, the value of exploring both farmer and advisor perspectives on behavior in the animal health context is demonstrated. Future interventions should look to target these three areas to overcome barriers and focus on factors that enable positive lameness practices to occur.

The bi-directional relationship between sleep and inflammation in muscular dystrophies: A narrative review.

Muscular dystrophies vary in presentation and severity, but are associated with profound disability in many people. Although characterised by muscle weakness and wasting, there is also a very high prevalence of sleep problems and disorders which have significant impacts on quality of life in these individuals. There are no curative therapies for muscular dystrophies, with the only options for patients being supportive therapies to aid with symptoms. Therefore, there is an urgent need for new therapeutic targets and a greater understanding of pathogenesis. Inflammation and altered immunity are factors which have prominent roles in some muscular dystrophies and emerging roles in others such as type 1 myotonic dystrophy, signifying a link to pathogenesis. Interestingly, there is also a strong link between inflammation/immunity and sleep. In this review, we will explore this link in the context of muscular dystrophies and how it may influence potential therapeutic targets and interventions.

Changing interventions in farm animal health and welfare: A governmentality approach to the case of lameness.

Lameness is a significant health and welfare issue in farmed animals. This paper uses a governmentality approach, which focuses on how a problem is made governable, to examine an emerging 'ecology of devices' introduced to intervene in, and attempt to reduce, on-farm incidence of lameness. These devices are associated with advisers who work with farmers on-farm; they enact lameness as a governable entity, are tools to assess the existence of lameness against established norms, and prescribe actions to be taken in response to evidence of lameness. In doing this they subjectify farmers and advisers into seeing and responding to lameness in particular ways. Using concepts of governmentality alongside other perspectives on the power relations and the simplifications and complexities involved in interventions in animal health and farm practice, the paper draws on in-depth research with advisers including vets and other paraprofessionals who work with farmers, and their cows and sheep. It explores how this set of devices introduces particular techniques and practices in lameness management, and produces farmer and adviser subjectivities. It then explores some of the problematics of this mode of governing lameness, including analysis of the limitations and unintended consequences of attempts to simplify lameness management. The paper concludes by arguing that its approach is valuable in analysing ongoing intensification of interventions in farming practices and in understanding the limits of such interventions and the unanticipated divergences from expected conduct.

Discovery and Development of the Quininib Series of Ocular Drugs.

The quininib series is a novel collection of small-molecule drugs with antiangiogenic, antivascular permeability, anti-inflammatory, and antiproliferative activity. Quininib was initially identified as a drug hit during a random chemical library screen for determinants of developmental ocular angiogenesis in zebrafish. To enhance drug efficacy, novel quininib analogs were designed by applying medicinal chemistry approaches. The resulting quininib drug series has efficacy in in vitro and ex vivo models of angiogenesis utilizing human cell lines and tissues. In vivo, quininib drugs reduce pathological angiogenesis and retinal vascular permeability in rodent models. Quininib acts as a cysteinyl leukotriene (CysLT) receptor antagonist, revealing new roles of these G-protein-coupled receptors in developmental angiogenesis of the eye and unexpectedly in uveal melanoma (UM). The quininib series highlighted the potential of CysLT receptors as therapeutic targets for retinal vasculopathies (e.g., neovascular age-related macular degeneration, diabetic retinopathy, and diabetic macular edema) and ocular cancers (e.g., UM).

Exploring farmers' understanding of and responses to endemic animal health and welfare issues in the UK.

BACKGROUND: This paper uses two endemic health conditions to explore farmer understandings of and responses to livestock health and welfare issues. METHODS: The findings are based on a survey of 42 livestock farmers in the north of England, exploring how they manage lameness in sheep and cattle and bovine viral diarrhoea in cattle. We identify similarities and differences in their approaches. RESULTS: Two themes emerge. (1) The importance of difference between animal types (i.e., beef cattle, dairy cattle and sheep), which highlights the 'complex' and 'multifactorial' nature of animal health and welfare. It is necessary to unpack this to understand the interplay of animal, resource and management issues in farmer responses. (2) Previous research has identified 'lack of knowledge' as a key welfare issue. Our findings reveal farmers are in fact seeking, acquiring and sharing knowledge on practices related to the management of animal health however individual circumstance and context influence how this translates in practice. CONCLUSION: Our research highlights the importance of integrating different perspectives and knowledges as a way of understanding and responding to animal health and welfare concerns. Facilitating knowledge exchange both within and between different groups and sectors is vital in achieving this.