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Probabilistic failure analysis of stochastically excited nonlinear structural systems with fractional derivative elements
Full text linkIn this paper, the application of the relaxed power spectral density (PSD) framework is developed for quantifying uncertainties in dynamical systems with fractional derivative elements. The proposed methodology offers a systematic treatment of uncertainties in spectrum-based stochastic simulation and their propagation for response determination of systems with memory-dependent or viscoelastic behavior. A key advantage of the framework lies in its ability to model the variability of estimated PSD functions using a non-parametric probabilistic representation, while explicitly accounting for frequency-domain correlations that are typically overlooked in conventional PSD-based estimates. First, a “relaxed” version of the power spectral density is derived by extracting statistical moments across ensembles of discretized PSD estimates. Next, frequency-dependent truncated normal distributions are employed to capture PSD uncertainties. Statistically compatible realizations are generated using three distinct sampling strategies: a single-variable inverse cumulative distribution function-based method for efficient sampling of marginal probability density functions, a multivariate Gaussian approach that incorporates cross-frequency covariance to capture global correlation structure, and an Ornstein–Uhlenbeck Markov process model, which reconstructs smoothly correlated PSD trajectories. The efficiency of the proposed approach is demonstrated by considering three representative case studies. These are a Duffing nonlinear oscillator with fractional damping, a tuned mass-damper-inerter system with nonlinear coupling characteristics, and a nonlinear vibration energy harvester under stochastic excitation. It is shown that by accounting for a comprehensive probabilistic treatment of the PSD, the proposed framework yields enhanced reliability analysis results of dynamical systems under spectral uncertainty
Finding the Goldilocks Zone: Retrieving Citation Context
Full text linkWe report on a first set of results from experiments undertaken to tackle the novel task of determining the optimal context window for extracting and contextualising citation instances within case law. The wider task of outcome prediction using AI tools cannot be undertaken without considering the role that citations play when new cases are being decided. This short paper aims to shine a light on the importance of this task and provide the foundation for developing AI tools to capture citations' context by examining a corpus of legal cases taken from the European Court of Human Rights. Our results show that there is an identifiable "Goldilocks Zone"of scoped paragraph-level context windows that attention can be focused on for extracting citation instances
Chromatin accessibility in MSC chondrogenesis, adult hip cartilage chondrocytes and osteoarthritis
No full textObjective: Cell type-specific gene expression programs are mediated by interactions between enhancers, transcription factors and gene promoters. Access to the DNA is regulated by the presence and modification state of chromatin. This study sought to reveal the chromatin accessibility of the cartilage chondrocyte genome and identify changes that occur in accessibility during both development from mesenchymal stem cells (MSC) and in osteoarthritis (OA). Method: Assay for Transposase-Accessible Chromatin using Sequencing (ATAC-seq) was performed on bone-marrow-MSC and MSC-derived differentiated chondrocytes, as well as primary chondrocytes isolated from 16 patients undergoing total hip replacement because of OA or due to a neck of femur fracture. Results: During MSC chondrogenesis we identified 138,005 open chromatin regions, with 20,979 regions undergoing increased accessibility. De novo established accessible regions were enriched at enhancer regions, defined previously by ChIP-seq, with key cartilage genes experiencing substantial chromatin reconfiguration often overlapping with SOX9 binding sites. In hip chondrocytes we identified 115,295 open chromatin regions, of which 1383 and 573 were more or less differentially accessible in OA. Comparison with a single cell ATAC-seq ATLAS identified accessible regions restricted to chondrocytes and established during chondrogenesis. Accessible regions were mapped to 320 OA-associated single nucleotide variants, many of which become accessible during chondrocyte development. Conclusions: This study illustrates the establishment of the chondrocyte chromatin landscape and identifies enhancer regions correlated with the cartilage transcriptome and associated with variants linked with cartilage disease OA
Nanomaterial-enhanced electrochemical biosensors for rifampicin monitoring in serum: towards precision tuberculosis therapy
Full text linkTuberculosis (TB) treatment is hampered by the pharmacokinetic variability of the cornerstone drug, rifampicin (RIF). This can lead to sub-therapeutic dosing, treatment failure, and the subsequent emergence of drug resistance. Therapeutic drug monitoring (TDM) is essential but is often inaccessible in high-burden, resource-limited settings due to its reliance on slow, expensive, and lab-based techniques like HPLC, while point-of-care systems offer a rapid and low-cost alternative. To address this critical gap, we have developed a low-cost, rapid, and scalable electrochemical biosensor for point-of-care RIF monitoring. The sensor platform integrates a highly selective molecularly imprinted polymer (MIP) with a highly porous gold (HPG) nanomaterial on a disposable printed circuit board (PCB) electrode, costing approximately £0.09 per unit. The HPG layer significantly enhances the electroactive surface area and provides exceptional resistance to biofouling, a critical feature for clinical utility. This allows the sensor to operate directly in complex biological matrices, demonstrating robust performance in undiluted human serum. The sensor achieves a clinically relevant detection range of 8–24 μg mL−1 with a limit of detection (LOD) of 0.848 μg mL−1 and a limit of quantification (LOQ) of 1.31 μg mL−1. This work presents a significant step towards democratizing TDM, offering a practical tool to personalize TB therapy and combat drug resistance at the frontline of patient care
Outcome of three dogs with respiratory epithelial adenomatoid hamartoma and chondroosseous respiratory epithelial adenomatoid hamartoma treated with radiotherapy
No full textIntranasal respiratory epithelial adenomatoid hamartomas (REAHs) and chondro-osseous respiratory epithelial adenomatoid hamartomas (COREAHs) are rare in dogs. Affected dogs are often treated surgically but published outcomes data are scant. Here, 3 cases are described. An 11-year-old Siberian Husky with advanced REAH underwent stereotactic radiosurgery (17 Gy); had no acute radiotoxicity and experienced short-lived clinical improvement before loss to follow-up. An 8-year-old mixed breed dog with advanced COREAH causing cribriform lysis received stereotactic body radiotherapy (SBRT) (30 Gy in 3 fractions); had no acute radiotoxicity, a strong partial response to treatment, and was euthanized 26 months after irradiation. A 5-year-old Border Collie with sinonasal COREAH and cribriform lysis was treated with 3D conformal radiotherapy (45 Gy in 12 fractions); the dog had stable disease for 18 months with ongoing follow up at the time of publication. These experiences provide evidence that REAH/COREAH could be radioresponsive with potential for prolonged survival
Modes of state-led globalization: a comparative case on Chinese and Turkish investments in Africa
Full text linkForeign investment is no longer driven solely by cost or market access but increasingly by strategic concerns such as resilience and security. This shift signals a transformation not towards de-globalisation, but towards state-led globalisation, where states actively shape overseas economic activity. Academic debates often focus narrowly on either state or market forces. To move beyond this dualism, this study applies the growth coalitions framework to examine how state-capital relations shape Chinese and Turkish investments in Africa. Drawing on case studies of Chinese industrial zones in Ethiopia and Nigeria, and Turkish construction projects in Ethiopia and Tanzania, it analyses project location and financing decisions. Interview data reveal that China relies heavily on state-owned enterprises to advance industrial upgrading abroad, while leaving private firms to act independently. In contrast, Turkey actively supports private firms through diplomatic outreach and creative financing. These differences reflect distinct domestic political economies and coalition structures. The findings highlight the need to consider how domestic state-capital relations drive global investment strategies, offering new insights into the geopolitical dynamics of state-led globalisation
Mammalian herbivory indirectly shapes savanna arthropod communities but only at very low or high levels
No full textSavanna ecosystems support unique biodiversity and provide livelihoods for millions of people. Yet, wild herbivores are in decline due to poaching and land-use change while livestock numbers are increasing. These changes in density and composition alter savanna vegetation. There are likely indirect cascading effects of altered vegetation on savanna arthropods, but our understanding is limited despite their pivotal role in ecosystem functioning. We evaluate how differences in mammalian herbivory affect terrestrial arthropods in a semiarid Kenyan savanna. We sampled ground-active arthropods (focusing on ants) in six herbivory treatments ranging from high-intensity herbivory to complete exclusion of large herbivores. Ant abundance and richness were not affected by herbivory treatments, but the community composition of ants and arthropods differed at extremely high and low levels of herbivory due to indirect impacts on vegetation. Community composition changes occurred under extremely high levels of herbivory because the resulting short-grass communities and patches of bare ground led to high species turnover in ants. By contrast, extremely low herbivory promoted woody encroachment that led to the loss of savanna specialists via both species turnover and nestedness. We conclude that cascading effects of mammalian herbivory play only a relatively small role in shaping savanna arthropod communities, except at extreme levels of herbivory. However, the occurrence of savannas with these extreme levels of herbivory, both high and low, is likely to increase in the future, which may lead to more widespread changes in ecosystem functioning as a consequence of shifts in arthropod community composition
Surgical fixation versus non-surgical care for children with a displaced medial epicondyle fracture of the elbow (the SCIENCE study): a multicentre, randomised controlled, superiority trial and economic evaluation
Full text linkBackground Displaced medial epicondyle fractures are among the most controversial injuries in children, with increasing trends towards surgical fixation despite little supporting evidence. Approximately half of affected children undergo surgical fixation, while others receive non-surgical care. The SCIENCE trial aimed to determine whether surgical fixation to restore the position of the bone provides superior functional outcomes and is cost-effective compared with non-surgical care. Methods We conducted a pragmatic multicentre, randomised, superiority trial across 59 hospitals in the UK, Australia, and New Zealand. Recruiting sites were secondary or tertiary care hospitals providing acute paediatric trauma care. Eligible participants were aged 7–15 years with a displaced medial epicondyle fracture and patients were excluded if the injury occurred more than 2 weeks prior, they had a medial epicondyle fragment that was incarcerated (trapped) within the joint, the injury was part of a complex elbow fracture (ie, extending into the joint), or there were additional fractured bones outside of the elbow. Participants were randomly assigned (1:1) to either surgical fixation or non-surgical care using a web-based randomisation software from Oxford Clinical Trials Research Unit, with minimisation (including a random element) stratified by centre and elbow dislocation status at presentation. Participants and their parents and carers could not be masked to treatment. Surgical fixation was performed under general anaesthesia and involved a surgical incision, restoration of the anatomical alignment, and fixing the fragment, typically with a screw or wires. Non-surgical care involved immobilisation of the elbow at approximately 90° of flexion using a cast, splint, or sling. Both groups were allowed mobilisation as pain allowed, although cast immobilisation beyond 4 weeks was discouraged. The primary outcome was upper limb function at 12 months, measured using the Patient Report Outcomes Measurement System (PROMIS) Upper Extremity Score for Children in the intention-to-treat population, which included all participants in the groups to which they were randomly assigned, irrespective of treatment received. Complications and serious adverse events were summarised in a safety (as-treated) population defined by treatment received. A within-trial economic evaluation was undertaken from the perspective of the UK National Health Service and Personal Social Services over a 12-month time period. The trial was registered with ISRCTN, ISRCTN16619778; recruitment is complete and extended follow-up to age 16 years is ongoing. Findings Between June 10, 2019, and Sept 22, 2023, 647 patients from 59 sites met the inclusion criteria. 146 patients were excluded (64 due to the injury being more than 2 weeks old and 24 because the epicondyle fragment was incarcerated within the joint), 161 families of children meeting the eligibility criteria declined to participate, and for five patients there was no clinician equipoise. 335 participants were randomly assigned to an intervention (166 to the non-surgical care group and 168 to the surgical fixation group) and one was immediately excluded due to a randomisation error. Primary outcome data were collected from 285 (85%) participants. 170 (51%) participants were female and 164 (49%) were male. Mean participant age at baseline was 11·7 years (SD 2·3). At 12 months post-randomisation, the PROMIS Upper Extremity score was 53·1 (SD 7·8) in the non-surgical care group and 54·3 (5·7) in the surgical fixation group (mean treatment difference, 1·57 [95% CI –0·01 to 3·14; p=0·052]). This estimate of treatment effect was below the clinically important difference specified (4 points), supporting the conclusion that a clinically important effect is unlikely. Additional episodes of surgery, either planned or related to complications, occurred in 24 participants in the surgical group and three in the non-surgical group. Among the 150 participants who underwent surgical fixation, there were 14 intraoperative complications from 13 (9%) participants, and seven participants had a postoperative complication (5% participants) each requiring surgery. Routine screw or wire removal was undertaken in a further 17 (11%) participants. From the 184 participants in the non-surgical group, there were five complications among four (2%) participants, three (2%) of which required additional surgery. The mean per patient cost from the NHS and Personal Social Services perspective was £2435 (95% CI 1812 to 3057) more for participants in the surgical fixation group with a mean per patient quality-adjusted life year difference of –0·008 (95% CI –0·039 to 0·024). The probability that surgical fixation is cost-effective at the £20 000 or £30 000 per quality-adjusted life year willingness-to-pay threshold was 0%. Interpretation The SCIENCE trial demonstrates that surgical fixation offers no clinical benefit and is not cost-effective compared with non-surgical care, while exposing children to avoidable surgical risks. These findings suggest that non-surgical care should be adopted as the default management strategy for these injuries, regardless of initial elbow dislocation status. Funding National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (17/18/02), with additional support from the NIHR Academy, Oxford NIHR Biomedical Research Centre, and the Starship Foundation (New Zealand)
Reprogramme the E. coli metabolism by engineering a functional carbon-fixation pathway
No full textBackground: Rising atmospheric CO₂ levels and their impact on climate change have intensified the need for innovative carbon capture and fixation strategies. The Calvin-Benson-Bassham (CBB) cycle, a central metabolic pathway in all photoautotrophic organisms and many autotrophic bacteria, plays a pivotal role in global carbon assimilation but is limited by the low catalytic efficiency of Rubisco. Results: Here, we engineered a complete, functional CBB cycle in Escherichia coli, by heterologously expressing up to 13 genes encoding phosphoribulokinase, α-carboxysomes, and inorganic carbon pumps. This bioengineering approach allowed E. coli to utilize atmospheric CO2 and led to increased levels of sugars such as ribose (4.94-fold) and xylitol (8.94-fold). Detailed metabolomic profiling of central carbon metabolism using gas chromatography-mass spectrometry (GC-MS) demonstrated that installation of the CBB cycle has a notable impact on the metabolic landscape of E. coli, resulting in substantial alterations in central carbon and amino acid metabolism. These findings deepen our understanding of the natural biological carbon-fixation pathway and its engineering in heterotrophic hosts. Furthermore, this work provides a versatile platform for evaluating and selecting efficient carbon-fixation modules, as well as assessing metabolic bottlenecks in engineered systems. Conclusion: These advances offer practical guidance for rational metabolic engineering in diverse organisms for biotechnological applications, including carbon sequestration, sustainable bioproduction, and crop improvement
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