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Large-order perturbation theory of linear eigenvalue problems
No full textWe consider a class of linear eigenvalue problems depending on a small parameter ϵ in which the series expansion for the eigenvalue in powers of ϵ is divergent. We develop a new technique to determine the precise nature of this divergence. We illustrate the technique through its application to four examples: the anharmonic oscillator, a simplified model of equatorially-trapped Rossby waves, and two simplified models based on quasinormal modes of Reissner-Nordstr¨om-de Sitter black holes
Metabolic engineering of Cupriavidus necator H16 for sustainable biomanufacturing
Get PDFUncoupling fuel and chemical production from the consumption of fossil resources is a fundamental challenge for sustainable development. In industrial biomanufacturing, this challenge is most often addressed by using heterotrophic microbes to convert plant biomass into value-added compounds. To improve the sustainability of industrial bioprocesses, a shift to alternative feedstocks is required. This includes the direct utilisation of excess atmospheric carbon dioxide (CO2), as well as other one carbon (C1) or two-carbon (C2) compounds which can be derived from abiotic CO2 reduction or alternative waste streams. As these feedstocks are broadly inaccessible to common industrial microbes, their bioconversion requires engineering specialised production strains.The facultative chemolithoautotroph Cupriavidus necator H16 (C. necator) holds demonstrable potential as a host strain for sustainable biomanufacturing, owing to its malleable metabolism and natural ability to utilise a wide range of feedstocks. To realise its potential, tailored molecular tools and extensive biological insights are needed. Addressing these requirements is the overarching aim of this thesis. A novel electroporation protocol was optimised, allowing for more rapid and efficient transformation of wildtype C. necator than previously attainable. This advancement, which accelerates the prototyping of synthetic DNA constructs, enabled the development of an efficient genome editing tool. The method uses homologous recombination and CRISPR-Cas counterselection to streamline the genomic manipulation of C. necator, facilitating the installation of new or enhanced cellular functions. During the development of this genome editing tool, the performance of several different genetic regulatory modules was characterised. These DNA parts are applicable in other biotechnological contexts, enabling the implementation of more complex genetic circuitry in C. necator. As an example, the implementation of a genetic logic gate was demonstrated.Strategies to improve growth and production from C1 and C2 substrates were also investigated. An evolutionary engineering approach was implemented to improve the growth rate of C. necator on formate, leading to the identification of evolved isolates with enhanced phenotypic traits. Genotypic analysis of these isolates revealed likely causative mutations, which could be harnessed for further metabolic engineering. Finally, the bioconversion of acetate to ethanol was investigated. Ethanologenic C. necator strains were constructed, recording improvements in titer, rate and yield over previous reports. Taken together, the findings documented in this thesis provide valuable tools, methods and insights relevant to C. necator engineering, thereby contributing to its development as a platform strain for sustainable biomanufacturing
Indecision and recency-weighted evidence integration in non-clinical and clinical settings
Get PDFBiases in information gathering are common in the general population and reach pathological extremes in paralysing indecisiveness, as in obsessive–compulsive disorder (OCD). Here we adopt a new perspective on information gathering and demonstrate an information integration bias whereby there is over-weighting of most recent information via evidence strength updates (ΔES). In a crowd-sourced sample (N = 5,237), we find that a reduced ΔES weighting drives indecisiveness along an obsessive–compulsive spectrum. We replicate this attenuated ΔES weighting in a second lab-based study (N = 105) that includes a transdiagnostic obsessive–compulsive spectrum encompassing OCD and generalized anxiety patients. Using magnetoencephalography (MEG), we trace ΔES signals to a late neural signal peaking at ~920 ms. Critically, highly obsessive–compulsive participants, across diagnoses, show an attenuated neural ΔES signal in mediofrontal areas, while other decision-relevant processes remain intact. Our findings establish biased information weighting as a driver of information gathering, where attenuated ΔES is linked to indecisiveness across an obsessive–compulsive spectrum
Detected Shifts Towards Drought‐Adaptive Strategies in the Amazon Forest Over the Last Four Decades
Get PDFThe Amazon Forest is undergoing rapid ecological shifts driven by intensifying drought, rising temperatures, and widespread anthropogenic disturbance. Yet the reorganization of vegetation functional strategies under climate stress remains poorly quantified at the biome scale. Here, we show that the temporal stability of canopy reflectance offers a sensitive remote proxy for sclerophylly—leaf toughness, a key indicator of conservative, drought‐adaptive plant strategies. By integrating ground‐based trait data (specific leaf area, SLA) from over 3000 trees across 448 plots in the Amazon‐Cerrado savanna transition zone with high‐resolution remote sensing imagery, we demonstrate that lower SLA—a well‐established proxy for conservative leaf strategies—is associated with reduced dry‐season variability in the blue band spectral reflectance of vegetation. Extending the analysis across 130 plots in nine Amazonian countries using 40 years of harmonised remote sensing data, we find that dry‐season reflectance variability has declined by ~34% (a drop of ~10 percentage points) since 1984, indicating a biome‐wide shift toward greater drought tolerance. This trend is most pronounced in the southern and eastern Amazon and closely tracks rising climate stress, particularly increased temperature, evaporative demand, and water deficit. If these patterns persist, much of the southern and eastern Amazon could reach reflectance‐stability levels comparable to transitional zones with the Cerrado savanna biome within the next three to four decades. Our results show signals of an early‐stage forest functional transformation that could reduce forest productivity and carbon uptake, increase vulnerability to fire, and diminish biodiversity. These findings highlight regions where early signs of reduced forest resilience are emerging, underscoring the need for spatially targeted conservation
Bayesian Network Meta‐Analysis With One or Two Continuous Outcomes Measured at Multiple Time Points Using Gaussian Random Walks With Drift
Get PDFNetwork meta‐analysis of randomized controlled trials is traditionally conducted on a single outcome measured at one time point. However, many trials also feature a secondary outcome and both outcomes may have been reported at multiple time points. Existing network meta‐analysis methods for synthesizing continuous outcome data from such trials focus on either the longitudinal data aspect or the multiple outcomes aspect, but not on both simultaneously. In this paper, we present two Bayesian network meta‐analysis models that account for the correlation of outcome measurements over time using Gaussian random walks with drift. The first model is suitable for a single continuous outcome measured at multiple time points, while the second model extends the first model to allow incorporation of a second outcome through cointegration of random walks. A simulation study to evaluate several statistical properties of these models is conducted. The results indicate that both proposed models produce unbiased estimates of relative treatment effect and drift parameters, as well as reasonable coverage. Furthermore, in some scenarios, using the cointegration model yields small gains in precision over using the single outcome model. Based on various performance measures, both proposed models also outperform an existing random walk network meta‐analysis model previously used by investigators to synthesize osteoarthritis trials data. The proposed models are illustrated with an application to trials evaluating treatments for knee and hip osteoarthritis. Both models are useful additions to existing tools available to investigators undertaking a network meta‐analysis of continuous outcome data at multiple time points
Event nouns in action: intercontinental supply and value chains in a frontier town (Londinium) according to Caesar and Tacitus
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Facile synthesis of zeolitic imidazolate framework coated glass microspheres
Get PDFIn this study we report a facile one-step, room temperature synthetic methodology for fabricating ZIF-8-coated phosphate-based glass (PBG) microspheres. ZIF-8 was grown in situ onto solid (non-porous) and porous P40 glass microspheres (composition 20Na2O-24MgO-16CaO-40P2O5, average diameter 153-172 µm), confirmed by PXRD and SEM analyses, with reaction times of one hour sufficient for coating onto solid P40 microspheres. An extended reaction time of 4.5 hours resulted in more homogeneous ZIF-8 coverage on the porous P40 microspheres. The ZIF-8 layer reduced microsphere degradation in water and slowed ion release from the microspheres, demonstrating a sacrificial protective coating effect of the ZIF-8. The ZIF-8 layer also enabled Zn2+ release (6.9-13.6 ppm over 7 days) and demonstrated improved methylene blue loading capacity, showing promise for pH-responsive drug delivery. This adaptable synthetic method to produce P40-based MOF composites highlights the potential synergistic benefits of combining PBG microspheres (bioactivity, tuneable degradation rates) and MOFs (high surface areas and porosity), offering an underexplored strategy to new MOF@PBG composites for drug delivery, antibacterial coatings and bone repair
Rapid diagnosis of skin and soft tissue melioidosis in children
Get PDFMelioidosis is an endemic infection caused by Burkholderia pseudomallei, found in tropical and subtropical regions. In resource-limited settings, culture-based diagnostics are often slow, delaying appropriate treatment, or unavailable. We conducted an interventional ambispective cohort study to assess the impact and diagnostic accuracy of the Active Melioidosis Detect Plus rapid diagnostic test (AMD-RDT) in Cambodian children with suspected skin and soft tissue melioidosis (SST-M). The retrospective cohort (July 2022–July 2023) received standard diagnostics; the prospective cohort (July 2023–December 2024) included AMD-RDT testing. Twenty-five retrospective culture-confirmed participants and 107 participants (31 culture-confirmed) in the prospective arm were analysed. Median time from pus collection to appropriate antibiotic initiation was 118.4 hours in the retrospective arm and 14.4 hours in the prospective arm (p = 0.057). Disseminated melioidosis workups were completed for 24% (6/25) and 80.6% (25/31) of retrospective and prospective participants respectively (p < 0.001), and detected two children with bacteraemia and three with intra-abdominal abscesses in the prospective arm. The AMD-RDT achieved a sensitivity of 90.3% (95% CI: 74.2–98.0%), specificity of 100% (95% CI: 95.3–100%), and an area under the receiver operating characteristic curve (AUC) of 0.95 (95% CI 0.89-1.00). Incorporating the AMD-RDT into the routine diagnostic pathway was associated with a reduction in time to effective antibiotic therapy and an increase in the proportion of participants completing a comprehensive diagnostic workup for systemic involvement. The high accuracy and rapid turnaround time support its use in resource-limited settings
Detection of Two High Pathogenicity Avian Influenza Virus (HPAIV) Subtypes, H5N1 and H5N5, in a Mass Mortality Event in Wild Seabirds and Co-Location With Dead Seals
Get PDFH5Nx Clade 2.3.4.4b high pathogenicity avian influenza viruses (HPAIVs) have been detected repeatedly in Great Britain (GB) since autumn 2020, with H5N1 dominating detections but with low level detection of H5N5 during 2025. Globally, these viruses have caused mass mortalities in captive and wild avian and mammalian populations, including terrestrial and marine mammals. H5N1 has been the dominant subtype, and whilst detections have overlapped temporally, occurrences have often been spatially distinct. Here, we report the detection of a mortality event in wild birds on the Norfolk coastline in the East of England, where H5N1 HPAIV was detected in five Great Black-backed Gulls (GBBGs; Larus marinus) and a Northern Fulmar (Fulmarus glacialis). Interestingly, at the same site, and as part of the same mortality event, a total of 17 GBBGs, one Herring Gull (Larus argentatus), one Atlantic Puffin (Fratercula arctica) and one Northern Fulmar tested positive for H5N5 HPAIV. Additionally, H5N5 was also detected in 17 co-located Grey Seal carcases (Halichoerus grypus). The H5N1 HPAIV from an infected bird belonged to genotype DI.2, closely related to contemporaneous detections in GB wild birds and poultry. In contrast, all H5N5 HPAIVs from birds and seals were Genotype I with a 22-amino acid stalk deletion in neuraminidase (NA) and the 627K polymorphism in PB2. This represents the first recorded instance in GB of two subtypes being detected within the same avian population at the same location. It is also the first mass detection of HPAIV H5N5 in mammals within GB. Potential infection mechanisms are discussed