1,357 research outputs found

    Gasdermins: a dual role in pyroptosis and tumor immunity

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    The gasdermin (GSDM) protein family plays a pivotal role in pyroptosis, a process critical to the body’s immune response, particularly in combatting bacterial infections, impeding tumor invasion, and contributing to the pathogenesis of various inflammatory diseases. These proteins are adept at activating inflammasome signaling pathways, recruiting immune effector cells, creating an inflammatory immune microenvironment, and initiating pyroptosis. This article serves as an introduction to the GSDM protein-mediated pyroptosis signaling pathways, providing an overview of GSDMs’ involvement in tumor immunity. Additionally, we explore the potential applications of GSDMs in both innovative and established antitumor strategies

    Life on a scale:Deep brain stimulation in anorexia nervosa

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    Anorexia nervosa (AN) is a severe psychiatric disorder marked by low body weight, body image abnormalities, and anxiety and shows elevated rates of morbidity, comorbidity and mortality. Given the limited availability of evidence-based treatments, there is an urgent need to investigate new therapeutic options that are informed by the disorder’s underlying neurobiological mechanisms. This thesis represents the first study in the Netherlands and one of a limited number globally to evaluate the efficacy, safety, and tolerability of deep brain stimulation (DBS) in the treatment of AN. DBS has the advantage of being both reversible and adjustable. Beyond assessing the primary impact of DBS on body weight, psychological parameters, and quality of life, this research is novel in its comprehensive approach. We integrated evaluations of efficacy with critical examinations of the functional impact of DBS in AN, including fMRI, electroencephalography EEG, as well as endocrinological and metabolic assessments. Furthermore, this work situates AN within a broader theoretical framework, specifically focusing on its manifestation as a form of self-destructive behavior. Finally, we reflect on the practical, ethical and philosophical aspects of conducting an experimental, invasive procedure in a vulnerable patient group. This thesis deepens our understanding of the neurobiological underpinnings of AN and paves the way for future research and potential clinical applications of DBS in the management of severe and enduring AN

    Heterogeneity in quiescent MĂĽller glia in the uninjured zebrafish retina drive differential responses following photoreceptor ablation

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    IntroductionLoss of neurons in the neural retina is a leading cause of vision loss. While humans do not possess the capacity for retinal regeneration, zebrafish can achieve this through activation of resident MĂĽller glia. Remarkably, despite the presence of MĂĽller glia in humans and other mammalian vertebrates, these cells lack an intrinsic ability to contribute to regeneration. Upon activation, zebrafish MĂĽller glia can adopt a stem cell-like state, undergo proliferation and generate new neurons. However, the underlying molecular mechanisms of this activation subsequent retinal regeneration remains unclear.Methods/ResultsTo address this, we performed single-cell RNA sequencing (scRNA-seq) and report remarkable heterogeneity in gene expression within quiescent MĂĽller glia across distinct dorsal, central and ventral retina pools of such cells. Next, we utilized a genetically driven, chemically inducible nitroreductase approach to study MĂĽller glia activation following selective ablation of three distinct photoreceptor subtypes: long wavelength sensitive cones, short wavelength sensitive cones, and rods. There, our data revealed that a region-specific bias in activation of MĂĽller glia exists in the zebrafish retina, and this is independent of the distribution of the ablated cell type across retinal regions. Notably, gene ontology analysis revealed that injury-responsive dorsal and central MĂĽller glia express genes related to dorsal/ventral pattern formation, growth factor activity, and regulation of developmental process. Through scRNA-seq analysis, we identify a shared genetic program underlying initial MĂĽller glia activation and cell cycle entry, followed by differences that drive the fate of regenerating neurons. We observed an initial expression of AP-1 and injury-responsive transcription factors, followed by genes involved in Notch signaling, ribosome biogenesis and gliogenesis, and finally expression of cell cycle, chromatin remodeling and microtubule-associated genes.DiscussionTaken together, our findings document the regional specificity of gene expression within quiescent MĂĽller glia and demonstrate unique MĂĽller glia activation and regeneration features following neural ablation. These findings will improve our understanding of the molecular pathways relevant to neural regeneration in the retina

    Inferences of Local Genetic Adaptation from Palaeolithic Hunter Gatherers

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    Ancient human genomes are an extremely powerful tool for exploring human demography and local genetic adaptation. Despite the thousands of genomes now available, there have been fewer amalgamated datasets focused on consistently processing samples created using different methods and filters. Therefore, I collated and processed a sample of 299 mostly publicly available ancient genomes sampling genetic diversity in Europe and recapitulating known clustering within ancient individuals. I made inferences of local genetic adaptation in 30 of the oldest Palaeolithic Hunter Gatherers, which were selected as they may reveal novel adaptations not detectable in younger individuals and or highlight earlier adaptations associated with the colonisation of Eurasia. I found many previously characterised candidates and one novel candidate in TCEA3. I also explored the advantage of incorporating ancient genomes in a test for Local Genetic Adaptation and observed a slight increase in candidates. Finally, I investigated functional annotations for the candidates of local genetic adaptation, highlighting some variants that may have influenced gene expression and disease risk and some which fall within Neanderthal- introgressed regions

    Lanthanide-doped upconversion nanoparticles (UCNPs) for biomedical applications

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    This thesis examines the need for new antibacterial materials to treat small colony variants (SCVs) of Staphylococcus (S.) aureus bacteria and their parental strains. While ZnO-based nanoparticles (NPs) activated by ultraviolet (UV) and short wavelength visible light have been researched for their antibacterial properties, the potential benefits of incorporating UCNPs to allow activation by near-infrared (NIR) light have been overlooked. This study aims to fill this research gap by comprehensively investigating the synthesis and performance of ZnO-coated lanthanide-doped upconversion nanoparticle (UCNP) composites activated by NIR light against S. aureus SCVs and parental strains. Furthermore, this research addresses the limited understanding of the potential risks associated with UV emission from UCNPs used as fluorescent probes in super-resolution microscopy (SRM). Despite extensive research on the usage of UCNPs as fluorescent probes for SRMs, the potential cytotoxic effects of UV emission from UCNPs have not been thoroughly studied. To advance cellular imaging techniques and ensure cellular viability, a comprehensive investigation of UV emission from UCNPs is necessary. This thesis aims to identify and quantify UV emission by UCNPs used in SRM and develop strategies to minimise UV emission and mitigate potential cytotoxic effects. These two main aims are addressed in three results chapters. The first aim, the focus of chapters 2 and 3, focuses on the synthesis UCNP@ZnO composites that can be activated by NIR light for antimicrobial photodynamic therapy (aPDT) applications against S. aureus SCVs and parental strains. Chapter 2 reports the synthesis and performance of these composites, showing these materials to be effective antibacterial therapies against S. aureus SCVs, while chapter 3 improves upon the performance of these composites by careful tuning of the UCNP core and provides enhancements to the ZnO shell composition to improve reactive oxygen species generation and add a second mode of action in the form of silver nanoparticles. The second aim of this research is covered in chapter 4, which reports an investigation into the UV emission from UCNPs used as fluorescent probes in SRM. The work posits the need to understand the UV emission properties of these UCNPs as knowledge of these and the potential for cytotoxic effects are crucial for optimizing cellular imaging experiments and ensuring accurate and reliable results. Chapter 4 identifies design features and compositions that can limit UV emission, thereby minimizing the risk of phototoxicity and advancing the field of cellular imaging. Overall, the findings from this research have the potential to contribute to the development of safer and more effective targeted antibacterial therapies and enhance the understanding of UV emissions in cellular imaging techniques.Thesis (Ph.D.) -- University of Adelaide, School of Chemical Engineering, 202

    Fuzzy Natural Logic in IFSA-EUSFLAT 2021

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    The present book contains five papers accepted and published in the Special Issue, “Fuzzy Natural Logic in IFSA-EUSFLAT 2021”, of the journal Mathematics (MDPI). These papers are extended versions of the contributions presented in the conference “The 19th World Congress of the International Fuzzy Systems Association and the 12th Conference of the European Society for Fuzzy Logic and Technology jointly with the AGOP, IJCRS, and FQAS conferences”, which took place in Bratislava (Slovakia) from September 19 to September 24, 2021. Fuzzy Natural Logic (FNL) is a system of mathematical fuzzy logic theories that enables us to model natural language terms and rules while accounting for their inherent vagueness and allows us to reason and argue using the tools developed in them. FNL includes, among others, the theory of evaluative linguistic expressions (e.g., small, very large, etc.), the theory of fuzzy and intermediate quantifiers (e.g., most, few, many, etc.), and the theory of fuzzy/linguistic IF–THEN rules and logical inference. The papers in this Special Issue use the various aspects and concepts of FNL mentioned above and apply them to a wide range of problems both theoretically and practically oriented. This book will be of interest for researchers working in the areas of fuzzy logic, applied linguistics, generalized quantifiers, and their applications

    mRNA Binding Proteins in the Heart

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    Cardiac diseases result in altered protein and gene expression levels due to altered signal transduction pathways. RNA binding proteins (RBPs) are an emerging group of post-transcriptional regulators that control RNA between protein and RNA levels. Analysing the role of RNA binding proteins in cardiac dysfunction would be vital in understanding the coordination of multiple post-transcriptional events during such diseases. However, the specific role of RBPs in controlling protein expression in the diseased myocardium is still not completely understood. Ribosomal sequencing and RNA sequencing was used to identify mTOR-dependent and translationally regulated transcripts in response to TAC surgery. Ybx-1 showed up to be one RNA binding protein that is upregulated only during pathological hypertrophy in our screen. Experiments in isolated cardiomyocytes in vitro showed that Ybx-1 depletion prevents cellular growth by inhibiting protein translation. Furthermore, Ybx-1 expression depends on mTOR signalling and is independent of mRNA transcription. Ybx-1 knockdown in vivo preserves heart function during pathological cardiac hypertrophy. eEF2 mRNA was identified as a potential mRNA that binds to Ybx-1 and is upregulated during cardiac hypertrophy. Cardiac hypertrophy involves upregulation of protein synthesis, and elongation factors such as eEF2 regulate it. Identifying the crosstalk between Ybx-1 and eEF2 can help understand how these factors contribute to cardiac dysfunction

    Cognitive control, bedtime patterns, and testing time in female adolescent students: behavioral and neuro-electrophysiological correlates

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    IntroductionShorter and/or disrupted sleep during adolescence is associated with cognitive and mental health risks, particularly in females. We explored the relationship between bedtime behavior patterns co-varying with Social Jet Lag (SJL) and School Start Times (SST) and neurocognitive performance in adolescent female students.MethodsTo investigate whether time of day (morning vs. afternoon), early SSTs and days of the school week can be correlated with neurocognitive correlates of sleep insufficiency, we recruited 24 female students aged 16–18 to report sleep logs, and undergo event-related electroencephalographic recordings on Monday, Wednesday, mornings, and afternoons. Using a Stroop task paradigm, we analyzed correlations between reaction times (RTs), accuracy, time of day, day of week, electroencephalographic data, and sleep log data to understand what relationships may exist.ResultsParticipants reported a 2-h sleep phase delay and SJL. Stroop interference influenced accuracy on Monday and Wednesday similarly, with better performance in the afternoon. For RTs, the afternoon advantage was much larger on Monday than Wednesday. Midline Event-Related Potentials (ERPs) yielded higher amplitudes and shorter latencies on Wednesday morning and Monday afternoon, in time windows related to attention or response execution. A notable exception were delayed ERP latencies on Wednesday afternoon. The latter could be explained by the fact that delta EEG waves tended to be the most prominent, suggesting heightened error monitoring due to accumulating mental fatigue.DiscussionThese findings provide insights into the interaction between SJL and SST and suggest evidence-based criteria for planning when female adolescents should engage in cognitive-heavy school activities such as tests or exams
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