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Pipeline to evaluate YAP-TEAD inhibitors indicates TEAD inhibition represses NF2-mutant mesothelioma
Get PDFAs the core, tumorigenic downstream effectors of the Hippo signalling pathway, YAP/TAZ and the TEAD family of transcription factors represent attractive targets for drug discovery efforts within cancer research. This is particularly true in the context of pleural mesothelioma, in which there are many recent preclinical developments and clinical trials evaluating the efficacy of TEAD inhibitors. The range of inhibitors has shown great promise, but comparisons of their performances are so far limited. Here, we develop a high-content pipeline that enables a comparative analysis of currently developed YAP/TAZ-TEAD inhibitors. We take advantage of isogenic cellular models that enable us to examine inhibitor specificity. We identify genetic compensation of the Hippo pathway transcriptional module, with implications for therapeutic targeting, and implement Cell Painting to develop a detailed morphological profiling pipeline that enables further characterisation, quantification, and analysis of off-target effects. Our pipeline is scalable and allows us to establish specificity and comparative potency within cancer-relevant assays in a clinically relevant cellular model of pleural mesothelioma.</p
Alterations in innate immune parameters and oxidative stress-related gene expression in an Indian major carp, Labeo rohita (Hamilton, 1822), infected with Citrobacter freundii
Get PDFThis study aims to explore the physiological and molecular responses of the Indian major carp, Labeo rohita, following experimental infection with the bacterium Citrobacter freundii, with a specific goal to assess innate immune alterations and oxidative stress mechanisms. Fish were divided into three groups: control, vehicle control, and bacteria-infected. Fish were intraperitoneally injected with C. freundii suspension at the dose of 1.2 × 102 CFU/mL at 0 day to evaluate disease progression. The activity of certain immune parameters and expression of oxidative stress-related genes were analysed at the time intervals of 2, 4, 6, 8, and 10 days after infection at 0 day. Serum biochemical analysis showed a significant (p < 0.05) increase in respiratory burst, myeloperoxidase, α-2 macroglobulin, antiprotease, and lysozyme activity, indicating the defence responses of the fish to microbial infections. The activity of carboxylesterase, alkaline phosphatase, acid phosphatase, catalase, and peroxidase decreased significantly (p < 0.05) at several time points, indicating alterations in physiological functions, suppressed immune system and reduced antioxidant capacity. Gene expression analysis revealed significant (p < 0.05) upregulation of oxidative stress-related genes, including glutathione peroxidase, superoxide dismutase, and catalase in liver and kidney of infected fish, highlighting a robust antioxidant response to counteract oxidative stress induced by bacterial infection. The findings provide insights into pathogenic mechanisms of C. freundii and its effects on health and immune response of L. rohita, contributing to the development of effective management strategies for bacterial infections in aquaculture systems. Furthermore, it may provide practical guidelines for fish farmers to implement preventive strategies aimed at disease control
Using electronic health records to identify computed tomography brain features associated with post-stroke dementia: A feasibility study
Get PDFBackgroundWe explored the feasibility of linking research datasets to electronic health records to identify acute stroke computer tomography (CT) brain features associated with post-stroke dementia.MethodsWe linked data from two existing research datasets of people who had a stroke. These datasets contained expert-coded features from CT brain scans. Participants were followed-up by linking to their electronic health records. Survival analyses were performed to identify prognostic factors associated with increased risk of post-stroke dementia. ResultsTwenty-one participants (11%, n=21/185) were identified as having dementia after stroke (median follow-up: 9 years 8 months). Presence of cerebral atrophy and moderate-to-severe white matter hyperintensities on acute stroke CT scans were associated with an increased risk of post-stroke dementia.DiscussionLinkage to electronic health records is a feasible method for studying dementia outcomes after stroke. This method can be applied to larger stroke populations to explore acute stroke imaging predictors in more detail
Induced Pluripotent Stem Cells for the Treatment of Lysosomal Storage Disorders
No full textLysosomal disorders (LSDs) are a group of rare metabolic disorders, with an overall incidence of 1:4800 to 1:8000 live births. LSDs are primarily caused by dysfunctional lysosomal enzymes, which typically lead to the progressive accumulation of substrates within cellular lysosomes. As a result, patients experience a wide array of somatic symptoms such as visceromegaly, cardiopulmonary abnormalities, and respiratory and urinary infections. Additionally, over two-thirds of LSD subtypes have a neurological component, and without treatment, patients experience neurodegeneration, cognitive decline, and life expectancies spanning infancy to adulthood. At present, there is no therapy that rescues the degenerative neuropathology of LSDs, and current developments, such as brain-targeted enzyme replacement therapy, hematopoietic stem cell transplantation, and even gene therapy, can only prevent further neurodegeneration. However, recent advancements involving induced pluripotent stem cells (iPSCs) have demonstrated that stem cells may harbor the potential to both recapitulate the phenotype of neuropathic LSDs in vitro, as well as serve as a vector for regeneration in vivo, by replacing cells and neurons damaged by disease progression. This review reports the current state of iPSC technology in LSD research, and the pathway by which iPSCs are translated from disease modeling to serving as a regenerative therapeutic for neuropathic LSDs in the clinic.</p
Marked Gender Inequity in the Invited Speakers at the European College of Veterinary Surgeons Annual Scientific Congress 2012-2022
No full textThe objective of this retrospective study was to explore gendered equity for invited speakers at the European College of Veterinary Surgery (ECVS) Annual Scientific Meeting between 2012-2022 when compared to speciality demographics for ECVS membership. Our sample populations included the European College of Veterinary Surgeons (ECVS) Diplomate membership, and all invited speakers at their Annual Scientific Meetings between 2012-2022.Data was extracted from Meeting Programs including year, speaker name, session type, and frequency of invitation. Authors were assigned a binary gender using a web-based algorithm to determine gender by a first name. The number and gender of new Diplomates each year between 1993-2023 was obtained from the ECVS Office and used as a comparison group to assess proportional representation amongst invited speakers. We found that women comprised 27% (249/924) of ECVS Diplomates in 2012 and 33.82% (312/924) in 2022. In this decade, there were 913 invited lectures delivered at ECVS Annual Scientific Meetings, 21% (188/913) were delivered by women. Women were particularly under-represented for higher prestige lectures including State of the Art (0%), Pre-Congress wet labs (0%) and Pre-Congress expert-led sessions (15.8%, 15/95). In conclusion, the proportion of invited speakers that were women at ECVS Scientific Meetings between 2012-2022 was 21%, despite women comprising >25% of ECVS Diplomate membership since 2012. Higher prestige sessions were heavily biased towards speakers being men. We suggest proactive commitment is needed to achieve gender equity in speaker invitations across all session types at ECVS Annual Scientific Meetings.<br/
Dairy cow performance is associated with longitudinal microRNA profiles
No full textModern high producing dairy cows are still affected by poor fertility and disease, despite improvements achieved through genetic selection programs. Additional biomarkers of health and performance traits in cattle could enhance animal welfare and profitability by allowing farmers to cull animals before problems occur. We performed pilot investigations of plasma microRNA (miRNA) profiles during early life as potential biomarkers associated with future performance in dairy cows. The latter included survival to two years of age, age at first calving, yield of milk, fat and protein, mastitis and lameness traits, conception rate, number of services per conception, and calving interval. Using qPCR, we obtained longitudinal measurements and ratios involving nine miRNAs (miR-126-3p, miR-127, miR-142-5p, miR-154b, miR-27b, miR-30c-5p, miR-34a, miR-363, miR-425-3p) in plasma samples from three age groups: calves (<1 month), heifers (14-23 months), and first lactation cows (29-35 months). Changes in miR-126-3p from calf to first lactation cow were associated with first lactation milk yield and second lactation milk somatic cell count (an udder health indicator). Moreover, the miR-127 to miR-30c-5p ratio in cows was associated with milk fat and protein yield in the first two lactations, whereas miR-142-5p levels and several miRNA ratios involving this miRNA, were associated with second calving interval (a cow fertility trait). Our results identified novel early life biomarkers that warrant further investigation to determine whether they may predict dairy cattle performance.</p
Characterization of bovine and ovine basal-out and apical-out ileum organoids
No full textOrganoids are three-dimensional stem cell-derived structures that differentiate into multiple cell types. Their capacity to self-organize, coupled with the presence of diverse cell types, means that organoids resemble their organ of origin in architecture and function. Organoids from intestinal tissues have been extensively used as a three-dimensional model for in vitro studies of the gut. However, they typically self-organize with basal-out polarity when cultured in a three-dimensional extracellular matrix scaffold, presenting a hurdle for experiments that require access to the apical epithelial surface. Methods to invert the surface polarity of intestinal organoids have been reported, but little information exists on how this change of polarity impacts gene expression and cell populations present within the organoids. To address this knowledge gap, we modelled both polarity states in intestinal organoids from two different ruminant species. Apical-out organoids largely retained the same gene expression profile as basal-out organoids. Moreover, a combination of RNA-seq and immunohistochemistry analyses demonstrated the retention of specific markers of enterocytes, enteroendocrine, goblet and tuft cells present in organoids of both polarity states. This study presents a comprehensive validation of apical-out ileal organoids, providing supporting evidence for the utility of this model in experiments that require access to the apical surface.</p
Disease-associated hepatocytes are predictive of outcomes and survival in MASLD beyond fibrosis staging
No full textClash of the titans:The Sino-American geopolitical rivalry at the 2022 and 2024 Olympics in Beijing and Paris
No full textThis paper concerns the demonstration of the diplomatic rivalry between the United States and the People’s Republic of China at the 2022 Winter Olympics in Beijing and the 2024 Summer Olympics in Paris. Two incidents at these sport mega-events reflect increasing geopolitical tensions between the established and emerging superpowers. These include the diplomatic boycott of the opening and closing ceremonies at Beijing 2022 and the doping allegations against several Chinese swimmers at Paris 2024. This research examines how American and Chinese media—The New York Times and The Global Times—relay the interstate conflicts at the two Olympics to each other and the international community. With reference to the debate on the decline of liberal internationalism as a theoretical backdrop, this work discusses the causes of the United States–China altercations at the two Olympics. With the rise of China, American hegemony in the liberal international order is being challenged. At the historical juncture when the American unipolarity starts to crumble slowly and a multipolar structure gradually begins to form, the two major sporting events in question duly reflect the divisive world politics. In this circumstance, unfortunately, Olympic journalism in the two rival nations further deepens this fissure
Can the use of silver nanoparticles in dental implants increase its antimicrobial potency? - systematic review
No full textBACKGROUND: Silver nanoparticles (AgNPs) is a promising nanotechnological solution to prevent microbial colonization on dental implants, offering a promising avenue for combating implant-related infections and improving long-term treatment outcomes.METHODS: Using manual search and electronic databases such as PubMed Advanced Search and Google Scholar, a methodical search was carried out from 2013 to 2023 utilizing keywords, and inclusion and exclusion criteria to find pertinent papers addressing the research question "Can the use of silver nanoparticles in dental implants increase its antimicrobial potency?". Critical Appraisal analysis for this review was done using risk of bias tool for in vitro studies: QUIN tool.RESULTS: Nine of the 122 articles that were retrieved underwent the three-step screening process before being chosen for the final analysis. QUIN Tool were used to evaluate the quality of the included in vitro studies. The summarized results from nine studies reveal the efficacy of AgNPs in inhibiting microorganisms and preventing biofilm formation on dental implants. In vitro tests demonstrate AgNPs' ability to hinder bacterial growth associated with peri-implantitis. Various techniques, including surface modifications and nanostructure incorporations, exhibit promising antibacterial effects.CONCLUSIONS: AgNPs show promise in inhibiting multidrug-resistant bacteria, enhancing dental implant biocompatibility, and reducing peri-implant diseases, benefiting clinical outcomes and limiting bacterial colonization.</p
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