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Temporary hepatic support by extra-corporeal liver cross-circulation
No full textThere is no temporary hepatic support system that can effectively bridge patients with acute or acute-on-chronic liver failure to either recovery of native liver function or allotransplantation. This has not been achieved by artificial and bio-artificial systems because they do not replicate the many, diverse, and deeply integrated roles of an intact liver. Extra-corporeal liver cross-circulation (ELC), in which a patient’s blood is perfused through a donor liver maintained outside the body on a machine, may provide more comprehensive replacement of hepatic function, whilst avoiding the limitations of auxiliary transplantation. A novel ELC system (‘metra-ELC’) has been developed and evaluated. The donor liver is initially perfused in isolation before connecting to the recipient. During this phase, the perfusate composition must be made safe for connection. Three techniques of ex situ renal replacement therapy during liver perfusion were assessed for this purpose: haemofiltration using a haemoconcentrator was selected for the metra-ELC protocol.The metra-ELC system was tested with healthy pigs for 3 hours, confirming feasibility in vivo. It was then evaluated for 24 hours using allografts to treat pigs with acute liver failure. ELC effectively replaced lost native hepatic detoxification, excretory, synthetic, metabolic regulatory, and immunologic functions.Xenografts are a potential source of livers for ELC. Transgenic pig livers (triple glycan knock-out; seven human transgene insertion; porcine endogenous retrovirus inactivation) were perfused ex situ for 48 hours with pooled human whole blood, demonstrating preserved graft viability. The mechanism of liver xenograft-associated thrombocytopenia was investigated during short-duration ex situ isolated xenoperfusion. ELC using transgenic pig livers was examined in the decedent model. Decedents 1 – 3 underwent ELC with their native livers intact for 72 – 84 hours. The xenografts consistently produced bile and augmented hepatocellular function. Decedent 4 underwent native hepatectomy, followed by 48 hours of ELC with maintenance of normal lactate, pH, international normalised ratio, ammonia, and minimal vasopressor requirement. Thrombocytopenia developed within one hour of starting ELC in all decedents.Phase-1 clinical trials will determine the safety and feasibility of the metra-ELC system using (i) deceased donor human livers declined for transplantation and (ii) transgenic pig livers to support patients with acute-on-chronic liver failure
Analysis of the molecular mechanisms of mitotic spindle assembly and checkpoint signalling using the HaloTag system
No full textTimely alignment and accurate chromosome segregation in mitosis are vital for genomic stability and are required to prevent the emergence of aneuploid cells, a hallmark of many cancers. Central to these processes are kinetochores, large protein complexes which connect mitotic chromosomes to spindle-associated microtubules and act as hubs for spindle assembly checkpoint (SAC) signalling. The SAC ensures that correctly bioriented chromosomes are discriminated from unaligned chromosomes in a process involving the mitotic kinases Aurora B and MPS1. These interact with and phosphorylate the kinetochore microtubule binding protein NDC80 and SAC scaffold protein KNL1, respectively. This thesis uses the synthetic HaloTag sequence integrated into the endogenous genomic loci encoding NDC80, KNL1 and the Aurora B activator and targeting protein INCENP to enable accurate visualisation and rapid PROTAC-mediated degradation in living cells. Using this system, the roles of these proteins in SAC activity, kinetochore function, and genomic stability were investigated. Integration of the mStayGold fluorescent marker into the MPS1 and BUB1 checkpoint proteins in these HaloTag backgrounds enabled the live readout of SAC activity. In metaphase, microtubule pulling forces separate Aurora B at the inner centromere from its targets at the outer kinetochore. Using super-resolution STED microscopy, I show that NDC80 at kinetochores and Aurora B and CPC Survivin/Borealin at inner centromeres are collapsed together in prometaphase and become spatially segregated in metaphase. In contrast, no discernible separation was detected between the distal and proximal ends of the kinetochore, marked by CENP-A and NDC80 respectively. Structure-guided analysis revealed that Aurora B localisation to inner centromeres is crucial for SAC signalling in prometaphase. Targeted degradation of NDC80 prevents microtubules from attaching to chromosomes, resulting in constitutive SAC signalling and delayed mitotic progression. By contrast, either degradation of the SAC scaffold KNL1 or the Aurora B activator INCENP reduced SAC activity, with KNL1 loss shortening mitosis. Proteomic analysis of INCENP-dependent Aurora B phosphorylation sites in mitosis identified the kinetochore subunit DSN1 and the inner centromere kinesin MCAK. The data presented in this thesis support a spatial separation model for Aurora B in SAC signalling and demonstrate an important role for NDC80 in silencing of the SAC
Dependency of fatigue resistance on roughness in WAAM printed carbon steel components
No full textThe fatigue resistance of rough components produced by wire‐arc additive manufacturing (WAAM) is highly sensitive to geometric discontinuities as surface undulations contribute to stress concentration where fatigue cracks initiate. This research investigates the fatigue resistance of WAAM plates made of S355 carbon steel by combining fatigue experiments on samples characterised by different roughness and finite element (FE) models. The experiments evaluated the fatigue lives of a range of rough specimens under constant amplitude cyclic loading. The as‐deposited surfaces were measured with high precision three‐dimensional laser scanning. A generalised notch stress (GNS) approach estimating the fatigue resistance of as‐deposited specimens is then developed. Based on parametric FE assessment, different surface roughness is studied and their influence on the fatigue resistance is computed, highlighting key correlations between the ten‐point roughness height and the fatigue strength
Commercial Group III–V Metal Alkoxide Catalysts for Selective Epoxide and Anhydride Ring Opening Copolymerization Delivering Poly(ester- alt -ethers)
No full textThe ring-opening copolymerization (ROCOP) of cyclic anhydrides (A) and epoxides (B) is a controlled route to alternating polyesters, with the best catalysts delivering high ester sequence (AB) selectivity. In contrast, very few catalysts can selectively enchain the same monomers to produce ester-alt-ether (ABB) sequences. Here, simple, commercial, homoleptic Zr(IV) catalysts (alkoxides and chloride) show faster rates, controlled polymerization and high selectivity in epoxide/anhydride ROCOP to selectively produce poly(ester-alt-ethers) (>95%); they outperform the best prior Zr(IV) coordination catalyst. Comparing the copolymerization rates and selectivity using a systematic series of homoleptic Groups III–V metal alkoxide complexes, all d0 configurations, reveals a metal structure-polymer linkage selectivity correlation. Plots of the polymer sequence selectivity (ABB) against the metal center Lewis acidity, as assessed by its hydrolysis constant (pK h), show a linear correlation, identifying the most selective catalysts for bothpoly(ester-alt-ether) and polyester production. High Lewis acidity catalysts (1 < pK h < 0.6) are best for poly(ester-alt-ethers) (ABB), while those with lower relative Lewis acidities (8.1 < pK h < 8.5) are selective for polyesters (AB) and intermediate acidity metal catalysts form polymers with mixed linkages. The discovery of simple, commercial selective catalysts for epoxide and anhydride copolymerization is an important advance relevant to future production of elastomers, surfactants and adhesives
Application of Electrical Resistance Probes for Corrosion Monitoring and Cathodic Protection Assessment of Offshore Structures
No full textAn innovative electrical resistance probe was developed for in‐situ, real‐time corrosion monitoring of offshore structures, featuring a 1.0 mm track thickness and five sensing tracks. The increased thickness improves compatibility with industrial materials, while the additional tracks provide a more qualitative assessment of non‐uniform corrosion. The probe's performance was evaluated under submerged exposure in natural seawater and across anodic to cathodic potentials, simulating galvanic couplings and varying levels of cathodic protection. Its monitoring results were benchmarked against conventional weight‐loss coupons, and the effect of corrosion product accumulation on probe functionality was examined. The probe delivered accurate corrosion rates and confirmed its reliability in natural seawater. The increased thickness extended service life and provided a corrosion‐depth sensitivity of 70 nm, while the greater number of tracks brought the exposed area closer to that of coupons, improving detection of non‐uniform corrosion. The probe also detected, in real time, variations in corrosion rate caused by interruptions in the cathodic protection system
Are Galliformes of the High Himalayas Well Protected? Identifying Conservation Priority Areas Using an Assemblage‐Level Approach
No full textSummary: Conservation efforts often focus on charismatic animals, such as large carnivores, while many other species that play important ecological roles receive little attention. In this study, we focus on a group of ground‐dwelling birds (Galliformes) that are common and ecologically important in the high‐altitude regions of the Indian Himalayas but are often overlooked in conservation planning centered on snow leopards. Using large‐scale camera‐trap surveys across 26,000 km², we examined which environmental factors influence where these bird species occur, identified areas with high species diversity and unique species, and assessed how well these areas are covered by existing protected areas. We found that vegetation cover and seasonal temperature changes strongly influence the distribution of these birds. Importantly, most areas with high species diversity and unique bird species fall outside the current protected area network in our study area. We also show that the transition zone between the Greater and Trans‐Himalaya is particularly important for conserving these birds, many of which live in landscapes managed primarily for snow leopard conservation. Our findings highlight the need to look beyond single flagship species and consider groups of co‐occurring, functionally important species to better protect mountain ecosystems
Prediction of relapse in myelin oligodendrocyte glycoprotein antibody-associated disease: external validation of the MOG-AR score
No full textBackground: Predicting relapses in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) when disability is relapse-dependent is crucial to guide treatment decisions including whether to treat from onset. MOG-AR, a relapse risk score, was recently developed in a Chinese cohort from disease onset. This study aimed to externally validate the MOG-AR score. Methods: MOGAD patients seen through the Oxford National NMO Service with ≥ 1-year disease duration and available data for MOG-AR score calculation (variables of age, sex, onset attack phenotype, treatment) were included. MOG-AR score and grade were calculated. Relapse occurrence at 3 years from onset was used as the primary outcome. MOG-AR performance was assessed by measures of discrimination and calibration. Results: We included 284 MOGAD patients with a 4.7-year median disease duration. Relapse occurred in 38% within 3 years of onset. Median MOG-AR score and grade were 11 (IQR 10–12) and 3 (3–3) for those who relapsed and 9 (8–11) and 3 (2–3) for those who did not. Observed proportion with relapse was 27%, 26%, 41%, and 53% for grades 1, 2, 3, and 4, respectively. Discrimination assessment by grade showed an area under the receiver operating characteristic curve of 0.58 (95% CI 0.52–0.63). Calibration assessment was consistent with overestimation of relapse probabilities. Conclusion: In a UK-MOGAD cohort, MOG-AR score showed suboptimal performance in predicting relapse over a 3-year period from onset. Further work to find clinically accessible predictive biomarkers and tools for a relapsing course would facilitate better treatment strategies near disease onset
Middle English Arthurian verse romances
No full textThis chapter considers the Middle English Arthurian verse romances, and the ways in which these texts interact with the genre of Middle English romance at large. First, the chapter explores the relationship between expected audiences and the choice to write in verse when considering Arthurian subject matter. The chapter then turns to romances usually designated as non-Arthurian, and asks: to what extent do Arthur and his knights creep into narratives set outside, beyond or without the Arthurian court, and what might this tell us about the cultural impact of Arthurian material in medieval England? Finally, a number of romance tropes – the fair unknown, the loathly lady, and intruders of all kinds – are used to show Middle English verse romance’s potential to both reinforce and disrupt Arthurian courtly values
Continuous-time data-driven barrier certificate synthesis
Get PDFWe consider the problem of verifying safety for continuous-time dynamical systems. Developing upon recent advancements in data-driven verification, we use only a finite number of sampled trajectories to learn a barrier certificate, namely a function which verifies safety. We train a safetyinformed neural network to act as this certificate, with an appropriately designed loss function to encompass the safety conditions. In addition, we provide probabilistic generalisation guarantees from discrete samples of continuous trajectories, to unseen continuous ones. Numerical results demonstrate the efficacy of our approach and contrast it with related results in the literature
International normative charts for twin weight, length, and head circumference at birth, by gestational age and sex: the Twin Neonatal Cross-Sectional Study of the INTERGROWTH-21st Project
Get PDFObjective: Assessing the size of twins at birth using charts developed for singletons may over diagnose small for gestational age in this sub-population. The study aimed to produce international, twin-specific, newborn size normative charts by gestational age and sex.Study Design: This longitudinal observational study in eight geographically diverse settings prospectively collected data between May 2009 and August 2013 from healthy pregnant women and their newborn twins. The participants are were enrolled as part of the INTERGROWTH-21st study, and recruited based on World Health Organization recommendations for evaluation of anthropometric measures. All the women met, in addition to the underlying population characteristics of low perinatal risk, strict individual criteria for a population at low risk of impaired fetal growth. Newborn weight, length and head circumference measures were collected independently in duplicate by two trained anthropometrists within 12 hours of birth using identical equipment and protocols at all sites. From 1,034 multiple pregnancies, after exclusions including conditions such as smoking, high maternal BMI, congenital malformations, the final sample was 864 twin newborns.Results: We have produced international normative charts for newborn twin size at birth. Most of the twins fall below the 50th centile of the INTERGROWTH-21st standards for singletons. There is also an increasing divergence between the 50th centiles of twins and singletons as gestational age increases towards term.Conclusion: Their clinical utility compared to the singleton standards, as a neonatal anthropometric screening tool, needs to be tested at scale, e.g, in cluster randomised studies