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  • Design of a graphene oxide-BODIPY conjugate for glutathione depletion and photodynamic therapy

    Reina, G.; Ruiz Estrada, Amalia; Richichi, B.; Biagiotti, G.; Giacomazzo, G.E.; Jacquemin, L.; Nishina, Y.; Ménard-Moyon, C.; Al-Jamal, W.T.; Bianco, A. (2022-01)
    Boron dipyrromethene derivates (BODIPYs) are promising photosensitisers (PSs) for cancer treatment using photodynamic therapy (PDT). This study investigates the functionalisation of graphene oxide (GO) with a BODIPY derivate for glutathione (GSH) depletion and PDT. The functionalisation of GO with a 3,5-dichloro-8-(4-boronophenyl) BODIPY via a diol derivatisation with the phenyl boronic acid moiety at the meso position of the BODIPY core, allowed to preserve the intrinsic properties of GO. We demonstrated that both chlorine atoms were substituted by GSH in the presence of glutathione transferase (GST), inducing a relevant bathochromic shift in the absorption/emission features and thus generating the active PS. Ex vitro assessment using cell lysates containing cytoplasmatic GST revealed the intracellular catalytic mechanism for the nucleophilic substitution of the GO-BODIPY adduct with GSH. Confocal microscopy studies showed important differences in the cellular uptake of free BODIPY and GO-BODIPY and revealed the coexistence of GO-BODIPY, GO-BODIPY-GS, and GO-BODIPY-GS2 species inside vesicles and in the cytoplasm of the cells after 24 h of incubation. In vitro biocompatibility and safety of GO and GO-BODIPY were evaluated in 2D and 3D models of prostate adenocarcinoma cells (PC-3), where no toxicity was observed up to 100 µg ml−1 of GO/GO-BODIPY in all treated groups 24 h post-treatment (cell viability > 90%). Only a slight decrease to 80% at 100 µg ml−1 was observed after 48 h of incubation. We demonstrated the efficacy of a GO adduct containing an α-chlorine-substituted BODIPY for the simultaneous depletion of intracellular GSH and the photogeneration of reactive oxygen species using a halogen white light source (5.4 mW cm−2) with a maximum in the range of 500–800 nm, which significantly reduced cell viability (<50%) after irradiation. Our study provides a new vision on how to apply BODIPY derivates and potentiate the toxicity of PDT in prostate and other types of cancer.
  • When stuff gets old: material surface characteristics and the visual perception of material change over time

    De Korte, Ellen E.M.; Logan, A.J.; Bloj, Marina (2022-11)
    Materials’ surfaces change over time due to chemical and physical processes. These processes can significantly alter a material’s visual appearance, yet we can recognise the material as the same. The present study examined the extent of changes the human visual system can detect in specific materials over time. Participants (N = 5) were shown images of different materials (Banana, Copper, Leaf) from an existing calibrated set of photographs. Participants indicated which image pair (of the 2 pairs shown) displayed the largest difference. Estimated perceptual scales showed that observers were able to rank the images of aged materials systematically. Next, we examined the role that global and local changes in material surface colour play in the perception of material change. We altered the information about colour and geometrical distribution in the images used in the first experiment, and participants repeated the task with the altered images. Our results showed significant differences between individual observers. Most importantly, participants’ ability to rank the images varied with material type. The leaf images were particularly affected by our alteration of the geometrical distribution. Together, our findings show the factors contributing to the perception of material change over time.
  • Using routine healthcare data to evaluate the impact of the Medicines at Transitions Intervention (MaTI) on clinical outcomes of patients hospitalised with heart failure: protocol for the Improving the Safety and Continuity Of Medicines management at Transitions of care (ISCOMAT) cluster randomised controlled trial with embedded process evaluation, health economics evaluation and internal pilot

    Moreau, L.A.; Holloway, I.; Fylan, Beth; Hartley, S.; Cundill, B.; Fergusson, A.; Alderson, S.; Alldred, David P.; Bojke, C.; Breen, Liz; et al. (2022-04)
    Introduction Heart failure affects 26 million people globally, approximately 900 thousand people in the UK, and is increasing in incidence. Appropriate management of medicines for heart failure at the time of hospital discharge reduces readmissions, improves quality of life and increases survival. The Improving the Safety and Continuity Of Medicines management at Transitions (ISCOMAT) trial tests the effectiveness of the Medicines at Transition Intervention (MaTI), which aims to enhance self-care and increase community pharmacy involvement in the medicines management of heart failure patients. Methods and analysis ISCOMAT is a parallel-group cluster randomised controlled trial, randomising 42 National Health Service trusts with cardiology wards in England on a 1:1 basis to implement the MaTI or treatment as usual. Around 2100 patients over the age of 18 admitted to hospital with heart failure with at least moderate left ventricular systolic dysfunction within the last 5 years, and planned discharge to the geographical area of the cluster will be recruited. The MaTI consists of training for staff, a toolkit for participants, transfer of discharge information to community pharmacies and a medicines reconciliation/review. Treatment as usual is determined by local policy and practices. The primary outcome is a composite of all-cause mortality and heart failure-related hospitalisation at 12 months postregistration obtained from national electronic health records. The key secondary outcome is continued prescription of guideline-indicated therapies at 12 months measured via patient-reported data and Hospital Episode Statistics. The trial contains a parallel mixed-methods process evaluation and an embedded health economics study.
  • The Bioarchaeology of Disability: A population-scale approach to investigating disability, physical impairment, and care in archaeological communities

    Bohling, Solange N.; Croucher, Karina T.; Buckberry, Jo (2022-09)
    Objective: This research introduces ‘The Bioarchaeology of Disability’ (BoD), a population-scale approach which allows for a comprehensive understanding of disability in past communities through a combination of palaeopathological, funerary, and documentary analyses. Methods: The BoD consists of three phases: 1) Contextualisation includes period-specific literature review; 2) Data collection consists of palaeopathological re-analysis of individuals with physical impairment and collation of mortuary treatment data; and 3) Analysis incorporates qualitative and quantitative comparison of the funerary treatment of individuals with and without physical impairment to explore contemporary perceptions of disability. Materials: The BoD is demonstrated through a case study investigation of disability in later Anglo-Saxon England (c.8th-11th centuries AD) which included four burial populations (Ntotal=1,543; Nimpaired=28). Results: Individuals with disability could be buried with normative or non-normative treatment (e.g., stone/clay inclusions, non-normative body positioning), and in marginal, non-marginal, and central locations. Conclusions: The overall funerary variation for individuals with disability was relatively slight, which may suggest that political and religious factors were influencing normative funerary treatment of disabled individuals. The funerary variability that was observed in disabled individuals was probably influenced by individual and community-specific beliefs. Significance: This research describes a population-scale approach to archaeological disability studies that can be replicated in other archaeological contexts. Limitations: Individuals with non-skeletal physical impairment (e.g., soft tissue, mental) cannot be analysed osteologically and are not considered by the BoD. Suggestions for further research: The BoD should be applied to different archaeological communities around the world to better understand disability in the past.
  • The osteological evidence for execution in Anglo-Saxon England

    Mattison, A.; Williams-Ward, Michelle L.; Buckberry, Jo; Hadley, D.M.; Holgate, R. (BAR Publishing, 2022)
    This paper reviews the osteological evidence for execution in Anglo-Saxon England, which, in the cases of modern analysis, can reveal considerable detail about the methods of decapitation, in particular, and it also provides a critical appraisal of the considerably less reliable antiquarian reports. We suggest that secure evidence for execution, principally decapitation, can be identified through modern osteological analysis but it is limited, and we also argue that assertions made in antiquarian excavation reports about apparent examples of execution need to be treated with caution.
  • The dark satanic mills: Evaluating patterns of health in England during the Industrial Revolution

    Buckberry, Jo; Crane-Kramer, G. (2022-12)
    Objective: this research seeks to investigate the impact the Industrial Revolution had on the population of England. Materials: Pre-existing skeletal data from 1154 pre-Industrial (1066–1700AD) and 4157 industrial (1700–1905) skeletons from 21 cemeteries (N = 5411). Methods: Context number, sex, age-at-death, stature and presence/absence of selected pathological conditions were collated. The data were compared using chi square, Kolmogorov-Smirnov, t-tests and logistic regression (α = 0.01). Results: There was a statistically significant increase in cribra orbitalia, periosteal reactions, rib lesions, fractures, rickets, osteoporosis, osteoarthritis, enamel hypoplasia, dental caries and periapical lesions in the industrial period. Osteomyelitis decreased from the pre-industrial to industrial period. Conclusion: Our results confirm the Industrial Revolution had a significant negative impact on human health, however the prevalence of TB, treponemal disease, maxillary sinusitis, osteomalacia, scurvy, gout and DISH did not change, suggesting these diseases were not impacted by the change in environmental conditions. Significance: This is the largest study of health in the Industrial Revolution that includes non-adults and adults and considers age-at-death alongside disease status to date. This data supports the hypothesis that the Rise of Industry was associated with a significant decline in general health, but not an increase in all pathologies. Limitations: This meta-analysis relies upon previously gathered data and diagnosis from a large number of researchers. Incomplete skeletons were often excluded from analyses. Few rural cemeteries were available for inclusion. Suggestions for further research: Data from unpublished and ongoing excavations should be investigated. Comparison with historical data is encouraged.
  • Routine omics collection is a golden opportunity for European human research in space and analog environments

    Cope, H.; Willis, Craig R.G.; MacKay, M.J.; Rutter, L.A.; Toh, L.S.; Williams, P.M.; Herranz, R.; Borg, J.; Bezdan, D.; Giacomello, S.; et al. (2022-10)
    Widespread generation and analysis of omics data have revolutionized molecular medicine on Earth, yet its power to yield new mechanistic insights and improve occupational health during spaceflight is still to be fully realized in humans. Nevertheless, rapid technological advancements and ever-regular spaceflight programs mean that longitudinal, standardized, and cost-effective collection of human space omics data are firmly within reach. Here, we consider the practicality and scientific return of different sampling methods and omic types in the context of human spaceflight. We also appraise ethical and legal considerations pertinent to omics data derived from European astronauts and spaceflight participants (SFPs). Ultimately, we propose that a routine omics collection program in spaceflight and analog environments presents a golden opportunity. Unlocking this bright future of artificial intelligence (AI)-driven analyses and personalized medicine approaches will require further investigation into best practices, including policy design and standardization of omics data, metadata, and sampling methods.
  • Multi-isotopic study of the earliest medieval inhabitants of Santiago de Compostela (Galicia, Spain)

    Perez-Ramallo, P.; Grandal-d´Anglade, A.; Organista, E.; Santos, E.; Chivall, D.; Rodriguez-Varela, R.; Gotherstrom, A.; Etxeberria, F.; Ilgner, J.; Fernandes, R.; et al. (Springer, 2022-10)
    Santiago de Compostela is, together with Rome and Jerusalem, one of the three main pilgrimage and religious centres for Catholicism. The belief that the remains of St James the Great, one of the twelve apostles of Jesus Christ, is buried there has stimulated, since their reported discovery in the 9th century AD, a significant flow of people from across the European continent and beyond. Little is known about the practical experiences of people living within the city during its rise to prominence, however. Here, for the first time, we combine multi-isotope analysis (δ13C, δ15N, δ18Oap, δ13Cap, and 87Sr/86Sr) and radiocarbon dating (14C) of human remains discovered at the crypt of the Cathedral of Santiago to directly study changes in diet and mobility during the first three centuries of Santiago’s emergence as an urban centre (9th-12th centuries AD). Together with assessment of the existing archaeological data, our radiocarbon chronology broadly confirms historical tradition regarding the first occupation of the site. Isotopic analyses reveal that the foundation of the religious site attracted migrants from the wider region of the northwest corner of the Iberian Peninsula, and possibly from further afield. Stable isotope analysis of collagen, together with information on tomb typology and location, indicates that the inhabitants of the city experienced increasing socioeconomic diversity as it became wealthier as the hub of a wide network of pilgrimage. Our research represents the potential of multidisciplinary analyses to reveal insights into the origins and impacts of the emergence of early pilgrimage centres on the diets and status of communities within Christian medieval Europe and beyond.
  • Proteomic features of skeletal muscle adaptation to resistance exercise training as a function of age

    Deane, C.S.; Phillips, B.E.; Willis, Craig R.G.; Wilkinson, D.J.; Smith, K.; Higashitani, N.; Williams, J.P.; Szewczyk, N.J.; Atherton, P.J.; Higashitani, A.; et al. (2022-09)
    Resistance exercise training (RET) can counteract negative features of muscle ageing but older age associates with reduced adaptive capacity to RET. Altered muscle protein networks likely contribute to ageing RET adaptation; therefore, associated proteome-wide responses warrant exploration. We employed quantitative sarcoplasmic proteomics to compare age-related proteome and phosphoproteome responses to RET. Thigh muscle biopsies were collected from eight young (25 ± 1.1 years) and eight older (67.5 ± 2.6 years) adults before and after 20 weeks supervised RET. Muscle sarcoplasmic fractions were pooled for each condition and analysed using Isobaric Tags for Relative and Absolute Quantification (iTRAQ) labelling, tandem mass spectrometry and network-based hub protein identification. Older adults displayed impaired RET-induced adaptations in whole-body lean mass, body fat percentage and thigh lean mass (P > 0.05). iTRAQ identified 73 differentially expressed proteins with age and/or RET. Despite possible proteomic stochasticity, RET improved ageing profiles for mitochondrial function and glucose metabolism (top hub; PYK (pyruvate kinase)) but failed to correct altered ageing expression of cytoskeletal proteins (top hub; YWHAZ (14-3-3 protein zeta/delta)). These ageing RET proteomic profiles were generally unchanged or oppositely regulated post-RET in younger muscle. Similarly, RET corrected expression of 10 phosphoproteins altered in ageing, but these responses were again different vs. younger adults. Older muscle is characterised by RET-induced metabolic protein profiles that, whilst not present in younger muscle, improve untrained age-related proteomic deficits. Combined with impaired cytoskeletal adhesion responses, these results provide a proteomic framework for understanding and optimising ageing muscle RET adaptation.
  • Interfacial cocrystallization using oily phase via liquid−liquid phase separation

    Sajid, Asim; Alsirawan, M.H.D. Bashir; Seaton, Colin C.; Swift, Thomas; Pagire, Sudhir K.; Vangala, Venu R.; Kelly, Adrian L.; Paradkar, Anant R. (2022-10)
    Cocrystals consist of two molecules bonded together in a single crystal lattice giving rise to wide applications including improving solubility of poorly soluble pharmaceuticals. Cocrystallization reaction occurs in the oily phase of liquid–liquid phase separation (LLPS) after it is mixed with coformers. Indomethacin–saccharin cocrystal formation was monitored in situ, and the kinetics of crystallization were determined. The crystallization rates show that the process can be proposed to prevent unwanted oily phase formation during LLPS.
  • A qualitative analysis of stressors affecting 999 ambulance call handlers' mental health and well-being

    Powell, Catherine; Fylan, Beth; Lord, Kathryn; Bell, F.; Breen, Liz (Emerald, 2022)
    Purpose The 999 ambulance call handler is critical in responding to emergency patient treatment; however, the call handlers are often a hidden component of the healthcare workforce and an under-researched group. The objective of this study is to understand stress triggers experienced by 999 ambulance call handlers that could lead to burnout and examine personal and organisational mechanisms and strategies which reduced the risk of burnout. Design/methodology/approach A single interview case study approach applying qualitative methods was undertaken. Participants were identified through a purposive sample of 999 ambulance call handlers with the Yorkshire Ambulance Service National Health Service Trust (UK). Participants were interviewed via telephone between July 2019 and September 2019. Findings In total, 18 staff participated in this study. Societal factors including public incivility and media representation and organisational factors, such as a demanding environment, lack of appreciation and career progression, training issues and protocols were key stressors. Organisational well-being services were helpful for some, but for others lacked accessibility and appropriateness. Positive public feedback and speaking with peers bolstered well-being. 999 ambulance call handlers suggested that sufficient breaks, co-design or feeding back on training and protocols and creating more informal opportunities to discuss ongoing everyday stressors as methods to reduce stress and burnout. Originality/value This paper explores a previously under researched area on stressors and potential burnout in 999 call handlers. This paper highlights the need for improved organisational support services and appropriate public and sector peer recognition of the role of ambulance 999 ambulance call handlers.
  • The MK2 cascade mediates transient alteration in mGluR-LTD and spatial learning in a murine model of Alzheimer's disease

    Privitera, Lucia; Hogg, Ellen L.; Lopes, M.; Domingos, L.B.; Gaestel, M.; Muller, Jurgen; Wall, M.J.; Corrêa, Sonia A.L. (2022-10)
    A key aim of Alzheimer disease research is to develop efficient therapies to prevent and/or delay the irreversible progression of cognitive impairments. Early deficits in long-term potentiation (LTP) are associated with the accumulation of amyloid beta in rodent models of the disease; however, less is known about how mGluR-mediated long-term depression (mGluR-LTD) is affected. In this study, we have found that mGluR-LTD is enhanced in the APPswe /PS1dE9 mouse at 7 but returns to wild-type levels at 13 months of age. This transient over-activation of mGluR signalling is coupled with impaired LTP and shifts the dynamic range of synapses towards depression. These alterations in synaptic plasticity are associated with an inability to utilize cues in a spatial learning task. The transient dysregulation of plasticity can be prevented by genetic deletion of the MAP kinase-activated protein kinase 2 (MK2), a substrate of p38 MAPK, demonstrating that manipulating the mGluR-p38 MAPK-MK2 cascade at 7 months can prevent the shift in synapse dynamic range. Our work reveals the MK2 cascade as a potential pharmacological target to correct the over-activation of mGluR signalling.
  • Genetic Prediction of Myopia in Different Ethnic Ancestries

    Ghorbani Mojarrad, Neema; Plotnikov, D.; Williams, C.; Guggenheim, J.A. (2022-09)
    Background: Myopia has been shown to have a complex mode of inheritance, being influenced by both genetic and environmental factors. Here, an introduction into myopia genetics is given, with the shortcomings of current genetic prediction for myopia discussed, including the proportionally limited research on genetic prediction in people of non-European ancestry. A previously developed genetic risk score derived from European participants was evaluated in participants of non-European ancestry. Methods: Participants from UK Biobank who self-reported their ethnicity as “Asian”, “Chinese”, or “Black” and who had refractive error and genetic data available were included in the analysis. Ancestral homogeneity was confirmed using principal component analysis, resulting in samples of 3500 Asian, 444 Chinese, and 3132 Black participants. A published refractive error GWAS meta-analysis of 711,984 participants of European ancestry was used to create a weighted genetic risk score model which was then applied to participants from each ethnic group. Accuracy of genetic prediction of refractive error was estimated as the proportion of variance explained (PVE). Receiver operating characteristic (ROC) curves were developed to estimate myopia prediction performance at three thresholds: any myopia (equal to or more than 0.75D), moderate myopia (between -3.00D and -4.99D) and high myopia (equal to or more than -5.00D). Odds ratios for myopia were calculated for the participants in the top 10th or 5th percentile of genetic risk score distribution, comparing them to the remainder of the population. Results: The PVE value for refractive error was 6.4%, 6.2%, and 1.5% for those with Asian, Chinese and Black ethnicity, respectively (compared to 11.2% in Europeans). Odds ratios for any myopia and moderate myopia development for those within the top 10th and 5th percentile of genetic risk were significant in all ethnic groups P<0.05). However, the genetic risk score was not able to reliably identify those at risk of high myopia, other than for participants of Chinese ethnicity (P<0.05). Conclusion: Prediction of refractive error in Asian, Chinese and Black participants was ~57%, 55% and 13% as accurate in comparison to prediction in European participants. Further research in diverse ethnic populations is needed to improve prediction accuracy.
  • Concordance of objectively-detected retinal nerve fiber bundle defects in en face OCT images with conventional structural and functional changes in glaucoma.

    Cheloni, Riccardo; Denniss, Jonathan (2022)
    To assess how objectively-detected defects of retinal nerve fibre bundle (RNFB) reflectance in en face OCT images relate to circumpapillary retinal nerve fibre layer thickness (cpRNFLT) and visual field defects. Cross-sectional study. 16 participants with early-glaucoma and 29 age-similar healthy controls, among which 22 had usable en face images to establish normative levels of RNFB reflectance. All participants underwent cpRNFLT scans, visual field examination and wide-field OCT. En face reflectivity was assessed objectively using the Summary of Multiple Anatomically-Adjusted Slabs (SMAS) method. En face defects were deemed concordant with cpRNFLT when they had at least one cpRNFLT point with p
  • A Combined Rheological and Thermomechanical Analysis Approach for the Assessment of Pharmaceutical Polymer Blends

    Isreb, Mohammad; Chalkia, Marianiki; Gough, Timothy D.; Forbes, Robert T.; Timmins, P. (MDPI, 2022-08)
    The viscoelastic nature of polymeric formulations utilised in drug products imparts unique thermomechanical attributes during manufacturing and over the shelf life of the product. Nevertheless, it adds to the challenge of understanding the precise mechanistic behaviour of the product at the microscopic and macroscopic level during each step of the process. Current thermomechanical and rheological characterisation techniques are limited to assessing polymer performance to a single phase and are especially hindered when the polymers are undergoing thermomechanical transitions. Since pharmaceutical processing can occur at these transition conditions, this study successfully proposes a thermomechanical characterisation approach combining both mechanical and rheological data to construct a comprehensive profiling of polymeric materials spanning both glassy and rubbery phases. This approach has been used in this study to assess the mechanical and rheological behaviour of heterogenous polymer blends of hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC) over a shearing rate range of 0.1–100 s−1 and a temperature range of 30–200 °C. The results indicate that HPC and HPMC do not appear to interact when mixing and that their mixture exhibits the mechanistic properties of the two individual polymers in accordance with their ratio in the mixture. The ability to characterise the behaviour of the polymers and their mixtures before, throughout, and after the glassy to rubbery phase transition by application of the combined techniques provides a unique insight towards a quality-by-design approach to this and other polymer-based solid dosage forms, designed with the potential to accelerate their formulation process through obviating the need for multiple formulation trials.
  • Introduction

    Ch'ng, E.; Chapman, H.; Gaffney, Vincent L.; Wilson, Andrew S. (Springer Nature, 2022-04)
  • Afterword

    Ch'ng, E.; Chapman, H.; Gaffney, Vincent L.; Wilson, Andrew S. (Springer Nature, 2022-04)
  • The face of Stonehenge: 3D surface scanning, 3D printing and facial reconstruction of the Winterbourne Stoke cranium

    Nilsson, O.; Sparrow, Thomas; Holland, Andrew D.; Wilson, Andrew S. (Springer Nature, 2022-04)
    Stonehenge is one of the world’s most iconic archaeological sites and yet we know relatively little about the people that created this important prehistoric monument. This chapter contributes to this narrative by reconstructing the face of a high-status male who was recovered during nineteenth-century excavation of a Neolithic Long Barrow. Situated in the barrow cemetery at Winterbourne Stoke, this site is important to the contextual setting and contemporary development of Stonehenge as a ceremonial and ritual centre. The chapter reports on the combination of digital bioarchaeology and visual heritage methods, together with forensic reconstruction, that transformed the physical remains of the individual into digital data that was manipulated for 3D printing; and subsequent anatomical and visual art interpretation to yield physical life-like characteristics. His facial features have been rebuilt on the 3D printed skull, muscle by muscle, to create a highly realistic face from the era. The aim of this project was to provide a tangible connection to the archaeology of the Stonehenge landscape and to the people that developed its ceremonial and ritual significance—narrowing the temporal distance through the emotional experience it means to gaze into the eyes of a Neolithic individual.
  • Manual/digital interactions in 'Project code-named Humpty'

    Johnson, Kate; Evans, Adrian A.; Sparrow, Thomas; Black, L.; Harman, Robert; Yang, D.; Wilson, Andrew S. (Springer Nature, 2022-04)
    ‘Project code-named Humpty’ is a performative art piece involving the creation, fragmentation, and reconstruction of a 2.7 m high classically inspired sculpture. It was conceived to complement an archaeological science research project setting out to explore the use of digital scanning technologies in artefact reconstruction. The statue’s form was free sculpted in clay over a period of four years. It was cast in a self-supporting cementitious material specifically for the purpose of ceremonial fragmentation and subsequent reconstruction by archaeologists. In this chapter, we explore the project’s human/machine intentions, interactions, development processes and their wider implications leading to fragmentation. We explore how 3D terrestrial laser scanning with photogrammetry was used to chart the creation of the sculptural form and how scans informed finite element analysis, essential for safe casting and fragmentation. We show how structured light scanning was essential to create a digital backup of the mould and how drone imagery documented fragmentation tests and 360° imaging recorded studio and quarry activity.

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