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Short-term diet intervention comprising of olive oil, vitamin D, and omega-3 fatty acids alters the small non-coding RNA (sncRNA) landscape of human sperm
No full textOffspring health outcomes are often linked with epigenetic alterations triggered by maternal nutrition and intrauterine environment. Strong experimental data also link paternal preconception nutrition with pathophysiology in the offspring, but the mechanism(s) routing effects of paternal exposures remain elusive. Animal experimental models have highlighted small non-coding RNAs (sncRNAs) as potential regulators of paternal effects. Here, we characterised the baseline sncRNA landscape of human sperm and the effect of a 6-week dietary intervention on their expression profile. This study involves sncRNAseq profiling, that was performed on a subset (n = 17) of the participants enrolled in the PREPARE trial: 9 from the control group and 8 from the intervention group. 5'tRFs, miRNAs and piRNAs were the most abundant sncRNA subtypes identified; their expression was associated with age, BMI, and sperm quality. Nutritional intervention with olive oil, vitamin D and omega-3 fatty acids altered expression of 3 tRFs, 15 miRNAs and 112 piRNAs, targeting genes involved in fatty acid metabolism and transposable elements in the sperm genome. PREPARE Trial registration number: ISRCTN50956936, Trial registration date: 10/02/2014.</p
“It was just amazing!” unstructured interactions following a planetarium and science shows
No full textVisits to informal learning environments such as science centers can enhance curiosity and understanding of scientific concepts. These environments offer activities like science and planetarium shows to engage their audiences. One way to understand visitors’ experiences in these environments is to investigate interactions. Previous research primarily focused on structured interactions such as guided tours, leaving the exploration of spontaneous, unstructured interactions understudied. In this research, museum practitioners audio-recorded unstructured interactions following science and planetarium shows during free-choice visits to a science center. Thematic analysis showed that although interaction time was short, it was positive and inquisitive in nature. Most questions were related to the content of the show and asked by children, with emotional reactions more prominent after the planetarium show. This exploratory pilot research adds to the body of knowledge on unstructured interactions between visitors and science center staff members, contributing to the understanding of effective science communication.</p
The multiplicities of drawing. An investigation through practice
No full textThis thesis approaches the edges of the skin of drawing as the sum of the marks that signify it, revealing its active and constantly transforming nature, and displacing the assumption of the surface as the meeting place and occurrence of drawing.In order to undertake this research, the thesis is developed along three fundamental axes: certain debates that have been sustained in post-structuralist thought; artistic and architectural references relevant to this study; and my personal practice as an artist and architect, carried out in a wide variety of contexts, supports, tools and technologies. To this end, on the one hand, the encounter between calligraphy and drawing is explored, from which arise the concepts of rhythm and the importance of the path of the trace. On the other hand, the limit between writing and drawing is questioned, revealing the eminently relational and insubstantial character of drawing, the need to consider the intersection between parts rather than the search for a totality, and the interruption of the trace's journey by name and significance. Time is also revealed as a constituent of drawing, leading to the experience of drawing through the assimilation of its non-presence and the synchronic drift to which the overlapping of its rhythms leads us. In this way, drawing is understood as the superimposition of differences that can only coexist in an unthinkable space, which is not that of order or surface, but that of heterotopia. Having introduced these specificities of the traces, which determine the eminently relational and insubstantial character of drawing, this thesis moves on to unfold the multiplicity of drawing. It explains how the skin of drawing, understood so far in terms of the two-dimensionality of the traces on the surface, expands its thickness in a spatio-temporal multiplicity that responds to the diversity of traces produced by the whole body and to the interaction with other contextual agents beyond those of the unconscious human body. Finally, the thesis focuses on a visual approach to the multiplicities of drawing, based on an understanding of the mobile grammar of its traces, considered as a sum of particles in perpetual movement, collision, and constant regeneration in their interaction with the world.<br/
Sexual satisfaction across cultures, genders, languages, and sexual orientations: validation of the Global Measure of Sexual Satisfaction
No full textSexual satisfaction can be important for overall well-being and has been described as a sexual right. Individual and cultural factors, such as gender identity and sexual orientation, may influence theways in which individuals describe, share, or experience their sexuality. The aims of the present study were to examine the factor structure of the five-item GlobalMeasure of Sexual Satisfaction (GMSEX) in a large sample of adults in relationships, to conduct measurement invariance tests to examine whether the GMSEX functions similarly across language-, country-, gender- and sexual orientation-based subgroups, and to evaluate its validity with sexuality and relationship- related outcomes.Results of a confirmatory analysis among 51,778 participants from42 different countries across five continents (Mage=32.39 years, SD= 12.52, 56.9% cisgender women) corroborated the proposed one-dimensional factor structure of the scale. Measurement invariance tests also indicated that the scale was fully invariant across gender- and sexual orientation-based subgroups, and partially invariant across language- and country-based subgroups. The GMSEX correlated negatively with masturbation frequency and relationship length and positively with the frequency of sexual activity. Our findings support the validity of the GMSEX as a short and reliable scale to measure sexual satisfaction across diverse samples.</p
Lung IL-13 gene signatures are associated with raised tissue eosinophils in COPD
No full textBackground: the role of eosinophils in COPD and their utility as biomarkers for cytokine targeting monoclonal therapies remains unclear. We investigated the distribution of eosinophils across different tissue compartments in COPD and analysed gene expression to understand the possible mechanistic drivers of eosinophilic inflammation in COPD.Methods: blood and BAL from ex-smoking volunteers with mild/moderate COPD (n=31) and healthy ex-smoking controls (n=20), and bronchial biopsy tissue in a subcohort (n=19 and n=8, respectively) was analysed. Differentially-expressed genes (DEGs) were characterised using RNASeq. Proteomic analysis of BAL was conducted using mass-spectrometry.Result: COPD subjects had more eosinophils in blood and lung tissue compared to controls, with increased eosinophil protein CLC/Galectin-10 in BAL. However, peripheral blood eosinophil counts related poorly to numbers in lung tissue (rho=-0.09192, p=0.3541) or proportions in BAL (rho=0.01762, p=0.4632). Tissue IL-5Rα expression was higher in frequent exacerbators and related to tissue eosinophils, but not peripheral blood eosinophils.Higher blood eosinophils were associated with DEGs that differed with compartment. Higher tissue eosinophil levels were associated with IL-13-induced DEGs including POSTN in bronchial brushes and CCL26 in bronchial biopsies. Gene-set enrichment analysis on data from brushings revealed significant enrichment of IL-4/IL-13, but not IL-5, pathways associated with eosinophil presence. Conclusion: eosinophilic lung inflammation is related to exacerbation frequency, but lung eosinophils are not predicted by blood eosinophil counts in COPD. Our data suggest IL-13-mediated pathways may be responsible for the presence of tissue eosinophils in COPD. Further work to establish more predictive biomarkers of lung eosinophil biology are required to unlock this axis to optimised treatment.<br/
A multi-omics approach to explore the epigenomic landscape of splenic marginal zone lymphoma (SMZL)
No full textSplenic marginal zone lymphoma (SMZL) is a rare, low-grade B-cell malignancy. Whilst often indolent in nature, a significant proportion of patients (70%) will require treatment. The biased usage of the IGHV1-2*04 allele is found in ~30% of SMZL patients and has been associated with histological transformation and poor survival. This subtype features ongoing Somatic Hypermutation (SHM) and frequent mutations in del(7q), KLF2, and NOTCH2, suggesting genetic and antigenic drivers; however, its molecular features remain understudied.The study aims to comprehensively explore the epigenomic landscape and features of SMZL using an integrated multi-omics analysis, with particular focus on the IGHV1-2*04 sub-type. Using a novel tumour-normal paired whole genome sequencing (WGS) dataset from 25 SMZL patients, somatic aberrations were identified across the genome, which contributed to a larger integrated SMZL cohort (n=294) with WGS, extended panel re-sequencing, methylation, transcriptomic, and chromatin-accessibility data. Integrated analysis with single-cell RNA and VDJ-seq data from SMZL (n=3) and normal spleens (n=2) further revealed intra-tumoral heterogeneity.The matched WGS validated key driver gene mutations in KLF2, NOTCH2, KMT2D, TNFAIP3, TRAF3, SPEN and TP53. Novel non-coding mutational hotspots in key B-cell regulatory genes were identified and confirmed by the re-sequencing panel (n=76/294), targeting genes such as BCL6 (21%, 16/76), PAX5 (14%, 11/76), BACH2 (13.5%, 10/76). Importantly, enrichment of an SBSSHM (p < 0.05) signature revealed a possible role of aberrant SHM in the generation of key driver regions and genes. Furthermore, the IGHV1-2*04 subtype showed the expected inferior time-to-first treatment (TTFT) (HR=1.63, CI:1.08-2.45, p=0.018) and intermediate levels of IGHV SHM (97-99.9% IGHV identity, p < 0.001). It was further shown that this subtype is enriched for molecular and genetic features associated with more aggressive disease, including: i) KLF2, NOTCH2, and TRAF3 mutations, and del(7q) (p< 0.01), ii) greater mutational burden (n>=2 mutations per case, p< 0.01), iii) elevated proliferative history (epiCMIT from methylation data, p=0.003), iv) deregulation (by RNA-seq and methylation data) of cell-cycle control pathways (G2M pathway ,FDR=0.02,E2F targets, FDR<0.01), v) higher global promoter methylation (High-M) in PRC2 targets (p=0.04), vi) evidence of PRC2 perturbation by over-representation of transcription factor binding sites (EZH2, SUZ12) in hypermethylated CpGs (FDR<.05) and vii) branching clonal trajectories with evidence of ongoing somatic hypermutation, resulting in divergent B-cell clonotypes. Overall, we present an analysis of novel datasets in SMZL, uncovering key functional pathways and features influencing clinical outcomes of the IGHV1-2*04 subtype. Findings further suggest selective pressures on the B-cell receptor, driven by lesions acquired through aSHM mechanisms. These insights may provide potential avenues for new targeted therapies. <br/
Is the unity of normativity safe?
No full textA guiding assumption of much recent work on normativity is that it is uniform across domains. Normative notions are to be understood in the same way whether they concern moral, epistemic, prudential, aesthetic, and so on matters. This assumption is widespread but also contentious. In epistemology, it is commonplace to analyse knowledge and, more recently, justification by appeal to modal notions; that is, in terms of what is possible. Justification is a normative notion that applies across domains. Given the uniformity assumption, we should expect modal notions to appear in analyses of justification in, say, ethics. But that is not what we find. Instead, the tendency there is to explain justification in terms of reasons. While there are many theories of reasons in circulation, modal notions do not figure prominently, if at all, in them. So, there is a mismatch between the way in which normative notions are understood in epistemology and in ethics. This chapter tries to resolve this situation by developing a novel theory of reasons—specifically, of how fundamental reasons relate to derivative reasons—that makes central appeal to modal notions. In this way, the chapter suggests, we can reconcile the way ethicists and epistemologists understand reasons and, in turn, justification, thereby preserving the uniformity assumption
How would you handle this?” The impact of embedding early patient and public involvement in a biomechanical computational engineering doctoral research project
No full textBackground: engineering is often described as a technology-driven field. However, whilst frameworks exist to engage with stakeholders, patient and public involvement (PPI) is not often undertaken in projects that have a quantitative methodology, such as engineering. This can have an impact on research quality, relevance, accessibility and experience. This is especially significant in a biomechanical engineering context where the end-user is often a person with an experience or living with a condition that the researcher does not have.Aim: this paper aims to provide a commentary on the first steps taken to embed PPI into a biomechanical engineering doctoral research project, and the outcomes and learnings that have come from this experience.Methods: three members of the public living with hand osteoarthritis (OA) were involved in the early-stage PPI consultations. These sessions aimed to openly discuss the hand OA lived-experience, current treatments and considerations for the project.Results and discussion: early-stage PPI allowed a deeper understanding of the hand OA lived experience and prompted further PPI activity within the biomechanical engineering research project. Subsequently, a long-term partnership with public contributors was established, shifting the project's focus from purely developing a computational model to addressing three PPI-identified priorities: (1) patient variability, (2) joint instability, and (3) raising hand OA awareness, using both computational modelling and public engagement methods. Though the number of contributors was small, it allowed for meaningful and long-lasting partnerships to be developed. Based on the learnings from this approach, eight recommendations were developed for researchers seeking guidance on integrating PPI in similar research. These include leveraging the power of storytelling, introducing PPI into the research as early as possible, investing in training and planning, establishing a meaningful partnership with members of the public, understanding the commitment, maintaining flexibility, providing consistent feedback and diversifying research efforts.Conclusion: this project has demonstrated PPI can inspire ideas and guide critical thinking and technical workflow, uncovering solutions that might not emerge without collaboration. Although the evidence-base is limited, we advocate that PPI has a place in quantitative-heavy research fields such as engineering, especially biomechanical engineering where people are often the end-users of research outcomes.</p
Cardiovascular disease burden and risk factor management in cancer survivors: insights from a multi-ethnic, socio-economically deprived urban population
No full textBackground: cardiovascular disease (CVD) burden and risk factor management among cancer survivors, especially in socioeconomically deprived, multiethnic populations, remain understudied. This study examines CVD burden and risk factor control in survivors of 20 cancer types within a diverse urban population.Methods: this matched cohort study used electronic health records from 127 urban primary care practices. Cancer survivors were matched to non-cancer comparators at a 1:4 ratio. Cancer and CVD diagnoses were defined using standard clinical code sets. Sociodemographic variables, lifestyle behaviours, blood pressure, cholesterol levels and statin prescriptions were analysed. Multivariable regression evaluated associations between cancer history, CVD prevalence and risk factor control.Results: the cohort included 18 839 cancer survivors (43% men, average age 64±15 years), with high ethnic diversity (48% White, 24% Black, 22% Asian) and high deprivation levels. Cancer survivors had elevated odds of all CVDs considered, independent of shared risk factors. Heart failure was more common in haematological (OR 2.12; 95% CI 1.44 to 3.09) and breast cancer survivors (OR 1.38; 95% CI 1.16 to 1.64). Patients with bladder (OR 1.50; 95% CI 1.20 to 1.87) and lung cancer (OR 1.44; 95% CI 1.09 to 1.87) had higher odds of ischaemic heart disease. Venous thromboembolism risk was highest in ovarian cancer (OR 5.72; 95% CI 3.54 to 9.32). Blood pressure control was slightly better in cancer survivors (OR 0.92; 95% CI 0.87 to 0.97), yet one in three patients did not meet guideline-directed targets. Statin use and cholesterol management were similar between survivors and controls, but disparities were observed within certain ethnic groups.Conclusion: cancer survivors have an elevated risk of CVD, with variations by cancer type and ethnicity. Despite comparable or slightly better control of major risk factors, a significant proportion of cancer survivors do not achieve guideline-recommended targets, highlighting the need for optimised management strategies, particularly in high-risk subgroups
Judicial review and the basic architecture of federalism
No full textFederalism can be characterized as a mode of governance in which final decision-making powers are ‘divided’ across different levels (e.g., federal, provincial, and municipal). The relationship between federalism, so-defined, and judicial review is philosophically and practically important. It is also, with some notable exceptions, surprisingly under-theorized. Many federalism scholars assume that federalism requires judicial review without exploring how other mechanisms could play courts’ intended roles. Many judicial review scholars assume that the justification for judicial review depends (at least primarily) on rights-based considerations. This work takes a different tack, offering positive reasons for judicial review in federal ‘division of powers’ cases largely independent of rights review. It argues that the basic commitments of and the incentive structure inherent in federal governance require a third party to play conflict resolution and border policing roles. It further argues that proposed non-judicial mechanisms are unlikely to fill those necessary roles. Well-designed, independent courts can do so, creating a strong defeasible case for judicial review in federal countries that is presently undefeated. This best case for judicial review’s fundamental concern with maintaining a division of powers should, however, lead courts in multiple paradigmatically federal countries to take different approaches to interpretation
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