324139 research outputs found
Sort by
Codification in the common law
No full textCodification is generally thought of as a feature of modern legal systems in the civil law world. However, codification is also used by common law systems, although there is a real question whether the form of ‘codification’ employed by common law legislators is comparable to the codification employed by civil law legislators. The focus of the discussion here will be on the role of codification in English private law, in particular contract law, where codification has been explored in the modern era, but abandoned. There may, however, still be a role for the intervention of codifying legislation to solve some of the problems faced within the general rules of English contract law
Do latitudinal variations in the transfer efficiency of the biological carbon pump exist?
No full textPublished studies on the latitudinal variability of the biological carbon pump (BCP)’s transfer efficiency –the fraction of exported particulate organic carbon (POC) flux reaching depth– paint an inconsistent global picture. Some report higher transfer efficiency in warm, subtropical oceans, while others suggest that it is higher in cold, high-latitude or equatorial upwelling regions. Resolving this contradiction matters: understanding large-scale and seasonally varying latitudinal patterns of POC flux is central to predicting oceanic carbon sequestration by the BCP and its sensitivity to climate change or the efficacy of CO2 removal strategies. Here, we argue that the disagreement stems not only from the intrinsic noisiness of the marine environment, but also from how the BCP has been historically observed: sparsely and unevenly using inconsistent sampling frameworks across research projects and without a standardised method to quantify POC flux attenuation with depth. Specifically, we pose the null hypothesis that there is no distinct geographic variation in BCP transfer efficiency. To test it, we compiled in situ POC flux time-series data from sediment traps, radionuclide disequilibria, and instantaneous estimates from UVP5 imagery, alongside fluxes of two ballast minerals (calcium carbonate and biogenic silica), across biogeographically distinct locations. Our analysis reveals that once large local uncertainties are accounted for, no statistically significant geographic variation in BCP transfer efficiency can be identified, an important negative result supporting the null hypothesis. While these findings do not preclude the existence of distinct spatial variations in transfer efficiency, they raise critical questions about the BCP and its observability. They also underscore the challenges involved and the need for sustained POC flux observations, standardisation of protocols, and intercalibration of technologies if we are to fully understand the processes controlling the BCP and its future evolution under global warming
Understanding hoarding behaviours in the context of homelessness
No full textObjectives: To examine cognitive beliefs associated with hoarding in the context of homelessness, focusing on fear of future material deprivation, and to compare housing‐related adversities across groups with hoarding difficulties, homelessness or both. Design: Cross‐sectional, three‐group comparative study. Methods: Adults in the UK/Ireland were recruited between July 2023 and April 2024 through third‐sector and clinical partners via online, postal and in‐person routes. Participants were grouped as hoarding difficulties with homelessness in the past 10 years (H&H; n = 47), hoarding difficulties without homelessness (HD; n = 43) and homelessness without hoarding difficulties (HM; n = 39). Hoarding difficulties were identified by professional referral and eligibility screening, mapping onto DSM‐5 criteria (self‐report endorsement of all criteria). Primary outcomes were Beliefs About Hoarding Questionnaire–Revised (BAH) subscales (fear of material deprivation, harm avoidance, attachment disturbance). Secondary outcomes included negative housing experiences, hoarding severity (SI‐R), depression (PHQ‐8), anxiety (GAD‐7), functioning (WSAS) and early material deprivation (EEMD). Mixed‐model ANOVA tested group differences in BAH subscales, and Kruskal–Wallis tested housing experiences. Results: A significant group‐by‐belief interaction emerged. Fear of material deprivation and attachment disturbance were higher in H&H and HD than in HM. Harm avoidance was highest in H&H. H&H reported more negative housing experiences than HD and did not differ from HM (H&H ≈ HM > HD). Exploratory analyses showed higher depression, anxiety and impairment in H&H. HD showed the greatest hoarding severity (SI‐R total, clutter, discarding), whereas excessive acquisition was similar in H&H and HD. Conclusions: Hoarding difficulties in homelessness contexts appear embedded in cumulative psychosocial vulnerability rather than explained by deprivation alone. Harm avoidance may be particularly salient when hoarding co‐occurs with homelessness, suggesting potential targets for formulation and intervention in homelessness services
Association of plasma ferritin and plasma iron at time of vaccination with the immune response to SARS-CoV-2 vaccination: a longitudinal cohort study
No full textIntroduction: Recent studies have shown a link between iron status and immune response following infection or vaccination. We aimed to investigate whether plasma ferritin and plasma iron concentrations at time of vaccination were associated with the development and temporal decay of immune response to SARS-CoV-2 vaccination over 6 months. Materials and methods: We used data from the Zurich SARS-CoV-2 Vaccine Cohort (n=572). Participants were recruited from a random sample stratified by age groups (18–64 years, >65 years) and vaccine types (Pfizer-BioNTech BNT162b2, Moderna mRNA-1273, Johnson & Johnson JNJ-78436735). Iron parameters were measured at baseline (prior to vaccination), whereas different immunity markers were measured at baseline, 4 weeks, 6 weeks, 3 months, and 6 months. We investigated the association between plasma ferritin and plasma iron levels and immunity markers using linear mixed-effect models, and estimated half-life based on linear decay models. Results: Plasma ferritin and plasma iron concentrations were within the normal physiological range, and the prevalence of iron deficiency (4.5%) and inflammation (2.3%) was low. For every 50 μg/L increase in plasma ferritin concentration, we observed a 5.2% increase in Anti-S IgG antibodies, and a 13.6-19.9% increase in neutralizing antibodies against the Ancestral, Delta, and Omicron BA1 viral variants. Similarly, the highest plasma ferritin quartile showed a 14.9% increase in Anti-S IgG antibodies, and a 47.1-82.2% increase in Anti-Ancestral, Anti-Delta, and Anti-Omicron neutralizing antibodies compared to the lowest quartile. Despite high concentrations at 6 months, shorter mean half-lives of Anti-S IgG antibodies were observed in the highest quartiles of plasma ferritin concentrations (Q3: 121.4 days; Q4: 109.8 days vs. Q1: 152.1 days). Plasma iron results were less consistent and generally no evidence for associations was found. Conclusion: In this predominantly iron-replete cohort, higher plasma ferritin at the time of vaccination was associated with stronger vaccination-induced humoral immune responses to SARS-CoV-2 over 6 months
The role of phenotypic heterogeneity in collective cell migration
No full textUnderstanding collective cell migration requires robust mathematical models that effectively bridge the gap between individual cell behaviours and population-level dynamics. This thesis develops and analyses a suite of mathematical models for cell invasion into extracellular matrix (ECM), that are systematically derived from individual-based frameworks to ensure consistency in the inclusion of key biological mechanisms. Beginning with a single cell type, a volume-filling framework is introduced that accounts for spatial constraints imposed by both cells and ECM. These effects are incorporated coherently across all migration and proliferation processes to investigate their influence on invasion speed and wave structure by comparison to existing models in the literature. To further these insights, a variational principle approach is developed through the lens of optimal control theory, that characterises a new and improved lower bound on the speed of cell invasion in multi-species systems.Building on the homogeneous foundation, the volume-filling model developed initially is then extended to incorporate phenotypic heterogeneity. Firstly, by introducing two distinct sub-populations: one specialising in movement and ECM degradation, and the other in proliferation. Secondly, by replacing discrete phenotypes with a continuum of states, allowing for a more flexible representation of phenotypic variation across diverse biological contexts, including tumour invasion and immune cell exhaustion. By exploring different environmentally-dependent phenotypic switching mechanisms, it is demonstrated that phenotypic switching fundamentally alters both the cell invasion dynamics and the structure of the travelling fronts. Overall, this work demonstrates the importance of systematically deriving population-level models from their individual-based counterparts and reveals that phenotypic heterogeneity plays a crucial role in shaping migration patterns. These insights highlight key features for consideration when modelling collective migration and help improve our understanding of cell invasion and its broader biological implications
Viral infections drive functional remodeling of ribosome-associated proteins
No full textViruses hijack host ribosomes to synthesize their proteins and have evolved various strategies to manipulate translation, including the association of numerous non-ribosomal proteins, known as ribosome-associated proteins (RAPs), with the core ribosome. However, current methods of capturing RAPs that associate transiently and/or in small amounts with ribosomes are suboptimal. To address this issue, we developed an enhanced ribosome affinity purification (eRAP) method that enables the capture of over 500 previously unreported RAPs. Using eRAP, we investigated whether the composition of ribosomes changes during infection by two very different viruses: herpes simplex virus 1 (HSV-1) and Sindbis virus (SINV). Our results revealed that viral infection does not substantially alter the composition of core ribosomes but does drive extensive remodeling of RAPs in a virus-specific manner. Functional analyses with SINV showed that several of these RAPs are critical for viral propagation. Additionally, we discovered that the RAP ASCC3 plays a novel role in promoting the expression of secretory proteins, including viral glycoproteins. This occurs independently of ASCC3’s canonical function of rescuing ribosome collisions. Together, our findings establish the ribosome as a dynamic regulatory hub that undergoes remodeling to achieve virus-specific translational output, highlighting the functional significance of ribosomal heterogeneity
Oral PrEP use among pregnant or parenting young women in South Africa: evidence from a large community-based implementation study
No full textBackground: The risk of HIV acquisition is heightened during pregnancy and early parenthood with the additional risk of vertical HIV transmission. While recent studies have improved our understanding of PrEP use among pregnant and breastfeeding women, further evidence is needed to inform the design of interventions that support sustained use, especially among young women who are pregnant or parenting. Methods: We analysed data from young women aged 15–29 years who initiated PrEP in an implementation study (FastPrEP) in Cape Town, South Africa. Logistic regression was used to examine the association between pregnancy or parenting status (≥ 1 living child) and PrEP discontinuation at 1- and 4-months post-initiation, based on pharmacy refill data. The primary exposure was currently pregnant or having a child (vs. not); secondary analyses stratified by age (15–24 vs. 25–29 years) among women who were pregnant/parenting. Models were adjusted for age and hypothesised explanatory factors were included in sensitivity analysis: service delivery location, contraceptive use, HIV risk perception, and relationship status. Results: Between August 2022 and June 2024 n = 4,876 young women initiated PrEP; 44% were pregnant/parenting (of which 10% were pregnant), and the median age was 21.6 years (IQR:18–25). At 1-month, women who were pregnant/parenting had higher odds of PrEP discontinuation (aOR:1.30, 95% CI:1.14–1.49). At 4-months this relationship persisted (aOR:1.41, 95% CI:1.12–1.78) compared with non-pregnant/parenting women. Among those pregnant/parenting, younger women (15–24 years) had higher odds of discontinuation at 1-month (aOR:1.31, 95% CI:1.08–1.58) and 4-months (aOR:1.41, 95%CI:1.02–1.96) compared to women aged 25–29. In the fully adjusted multivariable model, receiving PrEP in mobile clinics (aOR:0.71, 95% CI:0.61–0.82) vs. government clinics was associated with lower odds of early discontinuation. Conclusion: Young women who are pregnant/parenting face elevated risk of early PrEP discontinuation. Differentiated, life-stage and youth-responsive interventions, such as counselling, partner involvement, and integration with maternal and child health, or sexual and reproductive health services, are critical to improving PrEP persistence among this priority population. This population should be prioritised in the rollout of long-acting PrEP formulations, which may better align with their needs and reduce the burden of daily adherence
A repeat expansion in GOLGA8A is a major risk factor for atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions
No full textAtypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U) is neuropathologically characterized by aggregation of the FET family of proteins and clinically manifests as sporadic young-onset frontotemporal dementia. Here we describe a major risk locus on chr15q14 identified through a genome-wide association study in 59 pathologically confirmed aFTLD-U cases and 3,153 controls (lead single nucleotide polymorphism rs549846383, P = 5.85 × 10−21, odds ratio 26.7). When combined with data from 28 additional aFTLD-U cases, 3,712 controls and 3,215 individuals with other neurodegenerative diseases and by leveraging in-house and public long-read genome sequencing data from 1,715 individuals, we identified a tandem repeat expansion on the associated haplotypes in an intron of GOLGA8A. We found variation in repeat length, motif length, and motif sequence, with long CT-dimer expansions strongly associated with aFTLD-U. Although the functional consequence of this repeat remains unknown, its presence in nearly 60% of aFTLD-U cases points to a fundamental role in disease pathogenesis
The cytoskeleton regulates cytoophidium dynamics in Drosophila ovaries
No full textCytoophidia are filamentous structures composed of CTP synthase (CTPS) and were first identified in the ovarian cells of Drosophila. As a highly conserved, membraneless organelle present across all three domains of life, cytoophidia exhibit dynamic behaviors essential for cellular homeostasis and function. Previous studies have demonstrated that cytoophidia are actively transported from nurse cells to the oocyte, suggesting a potential role in Drosophila oogenesis; however, the molecular and cellular mechanisms governing cytoophidium dynamics remain poorly understood. In this study, we employ live-cell imaging to systematically characterize the spatiotemporal dynamics of cytoophidia and to investigate the underlying regulatory mechanisms. Our findings reveal that cytoophidium dynamics depend on key cytoskeletal components, including microtubules, microfilaments, and myosin II. Disruption of either microtubules or microfilaments results in the disassembly or depolymerization of macro-cytoophidia, underscoring the essential role of the cytoskeleton in maintaining cytoophidium integrity and facilitating proper assembly. Collectively, these results establish that microtubules, microfilaments, and myosin II are pivotal for regulating cytoophidium dynamics. This study provides novel insights into the mechanisms of cytoophidium transport and assembly, and lays a foundation for further investigation of their functional significance in Drosophila oogenesis
A Permeability-Based Model for Prediction of Freckling in Nickel Superalloy Single-Crystal Castings
No full textNickel superalloy single-crystal castings with dimensions representative of aero engine high-pressure turbine blades were manufactured to two casting conditions. Under conditions of low thermal gradient freckle chains of randomly oriented secondary grains arose on external casting surfaces. The number of freckle chains depended on the orientation of the crystal relative to the external casting surface. A permeability-based model of inward flow conductance through the semi-solid to sustain an upward rising plume of solute-enriched liquid at the mould wall forming a freckle is developed. The model accounts for both extrinsic casting and intrinsic material factors. It is discovered that by inclusion of the anisotropic permeability arising from the differing crystal orientations within individual castings and application of a new criterion for flow in the semi-solid, conductance to flow within the semi-solid local to the plume explains almost all variation in the number of freckles formed between individual castings. The model is applied to assess the effect of extrinsic and intrinsic parameters on flow conductance, ranking their relative significance