cometadata/datacite-rtg-text-other-reclassification-records huggingface dataset:
Magneto-optical Kramers-Kronig analysis
Creators: name: Levallois, Julien
name: Nedoliuk, Ievgeniia
name: Crassee, Iris
name: Kuzmenko, Alexey B.
Publisher: name: arXiv
Year: 2015
Subjects: subject: Strongly Correlated Electrons (cond-mat.str-el)
subject: Mesoscale and Nanoscale Physics (cond-mat.mes-hall)
subject: FOS: Physical sciences

description: We describe a simple magneto-optical experiment and introduce a magneto-optical Kramers-Kronig analysis (MOKKA) that together allow extracting the complex dielectric function for left- and right-handed circular polarizations in a broad range of frequencies without actually generating circularly polarized light. The experiment consists of measuring reflectivity and Kerr rotation, or alternatively transmission and Faraday rotation, at normal incidence using only standard broadband polarizers without retarders or quarter-wave plates. In a common case, where the magneto-optical rotation is small (below $\sim$ 0.2 rad), a fast measurement protocol can be realized, where the polarizers are fixed at 45$^\circ$ with respect to each other. Apart from the time-effectiveness, the advantage of this protocol is that it can be implemented at ultra-high magnetic fields and in other situations, where an \emph{in-situ} polarizer rotation is difficult. Overall, the proposed technique can be regarded as a magneto-optical generalization of the conventional Kramers-Kronig analysis of reflectivity on bulk samples and the Kramers-Kronig constrained variational analysis of more complex types of spectral data. We demonstrate the application of this method to the textbook semimetals bismuth and graphite and also use it to obtain handedness-resolved magneto-absorption spectra of graphene on SiC.
description: 11 pages, 4 figurs
Target profiling of PARP inhibitors and necroptosis inhibitors using photoaffinity labelling
Creators: name: Howard, Ryan Thomas
Publisher: name: Imperial College London
Year: 2020

description: Target profiling of a small molecule therapeutic is essential to fully understand how that compound works in the clinic. Photoaffinity labelling (PAL) has become a widely utilised strategy for in-cell target identification campaigns for reversible, small molecule drugs. After an overview of target profiling and PAL, this Thesis discusses the application of PAL to two classes of molecules with incomplete target profiles. The Thesis focusses initially on the generation of the first photo-activatable probe for inhibitors of the PARP family of enzymes, PARPYnD, based on a novel anti-cancer PARP1/2/6 inhibitor AZ0108 with unexplained off-target toxicity. The design, synthesis and validation of the probe is discussed, along with the application of PARPYnD to PAL studies. Herein, simultaneous live-cell target engagement of PARP1/2 is shown for the first time by a photo-activatable probe, and this labelling is used to quantify live-cell engagement of these PARPs by known PARP inhibitors in competitive PAL experiments. For AZ0108 and clinical PARP inhibitor olaparib, novel off-targets are identified, demonstrating the power of PAL to capture weaker, secondary binders. Finally, PARPYnD fails to label PARP6 in live cells, but is able to label recombinant PARP6, highlighting a biomolecular disparity that raises questions about the proposed mechanism of action of AZ0108. PAL is then applied to a novel series of inhibitors of necroptosis, an inflammatory form of cell death, with an unknown mechanism of action. Design and synthesis of cell-active photo-activatable probe 7PQYnD1 is presented, along with the development of a bespoke live-cell necroptosis assay to evaluate necroptosis inhibitors in-house. 7PQYnD1 is then applied to the PAL workflow and five bona fide target proteins are identified through proteomics. Preliminary functional analysis of these hits is then undertaken to begin to identify the target interaction(s) responsible for the anti-necroptosis phenotype of these compounds.
Spleen Tyrosine Kinase (Syk) Mediates IL-1β Induction by Primary Human Monocytes during Antibody-enhanced Dengue Virus Infection
Creators: name: De Silva, Aravinda M.
name: Callaway, Justin B.
name: McKinnon, Karen P.
name: Smith, Scott A.
name: Crowe, James E.
name: Ting, Jenny P.Y.
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2015

description: Approximately 500,000 people are hospitalized with severe dengue illness annually. Antibody-dependent enhancement (ADE) of dengue virus (DENV) infection is believed to contribute to the pathogenic cytokine storm described in severe dengue patients, but the precise signaling pathways contributing to elevated cytokine production are not elucidated. IL-1β is a potent inflammatory cytokine that is frequently elevated during severe dengue, and the unique dual regulation of IL-1β provides an informative model to study ADE-induced cytokines. This work utilizes patient-derived anti-DENV mAbs and primary human monocytes to study ADE-induced IL-1β and other cytokines. ADE of DENV serotype 2 (DENV-2) elevates mature IL-1β secretion by monocytes independent of DENV replication by 4 h postinoculation (hpi). Prior to this, DENV immune complexes activate spleen tyrosine kinase (Syk) within 1 hpi. Syk induces elevated IL1B, TNF, and IL6 mRNA by 2 hpi. Syk mediates elevated IL-1β secretion by activating ERK1/2, and both Syk and ERK1/2 inhibitors ablated ADE-induced IL-1β secretion. Maturation of pro-IL-1β during ADE requires caspase-1 and NLRP3, but caspase-1 is suboptimally increased by ADE and can be significantly enhanced by a typical inflammasome agonist, ATP. Importantly, this inflammatory Syk-ERK signaling axis requires DENV immune complexes, because DENV-2 in the presence of serotype-matched anti-DENV-2 mAb, but not anti-DENV-1 mAb, activates Syk, ERK, and IL-1β secretion. This study provides evidence that DENV-2 immune complexes activate Syk to mediate elevated expression of inflammatory cytokines. Syk and ERK may serve as new therapeutic targets for interfering with ADE-induced cytokine expression during severe dengue.
Structural Basis of a Key Factor Regulating the Affinity between the Zonula Occludens First PDZ Domain and Claudins
Creators: name: Nomme, Julian
name: Antanasijevic, Aleksandar
name: Fanning, Alan S.
name: Caffrey, Michael
name: Lavie, Arnon
name: Anderson, James M.
name: Van Itallie, Christina M.
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2015

description: The molecular seal between epithelial cells, called the tight junction (TJ), is built by several membrane proteins, with claudins playing the most prominent role. The scaffold proteins of the zonula occludens family are required for the correct localization of claudins and hence formation of the TJ. The intracellular C terminus of claudins binds to the N-terminal PDZ domain of zonula occludens proteins (PDZ1). Of the 23 identified human claudin proteins, nine possess a tyrosine at the −6 position. Here we show that the claudin affinity for PDZ1 is dependent on the presence or absence of this tyrosine and that the affinity is reduced if the tyrosine is modified by phosphorylation. The PDZ1 β2-β3 loop undergoes a significant conformational change to accommodate this tyrosine. Cell culture experiments support a regulatory role for this tyrosine. Plasticity has been recognized as a critical property of TJs that allow cell remodeling and migration. Our work provides a molecular framework for how TJ plasticity may be regulated.
Tongbian decoction restores intestinal microbiota and activates 5-hydroxytryptamine signaling: implication in slow transit constipation
Creators: name: Wang, Yujuan
name: Han, Xiaojuan
name: Si, Xianghuan
name: Qian, Yunzhi
name: Li, Hongjia
name: Lv, Na
name: Li, Dongna
name: Xu, Tianshu
name: Hua, Yuanqing
Publisher: name: Frontiers Media SA
Year: 2024

description: Introduction Slow transit constipation (STC) is a type of functional constipation. The detailed mechanism of STC, for which there is currently no effective treatment, is unknown as of yet. Tongbian decoction (TBD), a traditional Chinese medicinal formula, is commonly used to treat STC in clinical settings. However, the potential impact of TBD on the management of STC via modulation of the gut microbiota remains unclear. Methods Pseudo-germ-free rats were constructed after 6 days of treatment with bacitracin, neomycin, and streptomycin (abbreviated as ABX forthwith). Based on the successful construction of pseudo-germ-free rats, the STC model (ABX + STC) was induced using loperamide hydrochloride. After successful modeling, based on the different sources of donor rat microbiota, the ABX + STC rats were randomly divided into three groups: Control → ABX + STC, STC → ABX + STC, and STC + TBD → ABX + STC for fecal microbiota transplant (FMT). Body weight, fecal water content, and charcoal power propelling rate of the rats were recorded. Intestinal microbiota was detected by 16S rRNA sequencing, and the 5-hydroxytryptamine (5-HT) signaling pathway was examined by western blots, immunofluorescence, and immunohistochemical analysis. Results After treatment with fecal bacterial solutions derived from rats treated with Tongbian decoction (TBD), there was an increase in body weight, fecal water content, and the rate of charcoal propulsion in the rats. Additionally, activation of the 5-hydroxytryptamine (5-HT) signaling pathway was observed. The 16S rRNA sequencing results showed that the fecal bacterial solution from TBD-treated rats affected the intestinal microbiota of STC rats by increasing the proliferation of beneficial bacteria and suppressing the expansion of harmful bacteria. Conclusion Our study showed that TBD alleviated constipation in STC rats by modulating the structure of the intestinal microbiota.
(3864) James Grant Bisset
Creators: name: Professions, Victorian
Publisher: name: University of Oxford
Year: 2022
Subjects: subject: 220201 Business and Labour History
subject: FOS: Philosophy, ethics and religion
subject: History
subject: 140203 Economic History
subject: FOS: Economics and business

description: This three-year research project began in January 2014 and investigated whether, during the Victorian period, the professions formed a distinct self-sustaining social group with its own mores and values. The project looked at 16,000 individuals drawn from census data for Alnwick, Brighton, Bristol, Dundee, Greenock, Leeds, Merthyr Tydfil, Morpeth, and Winchester. The research project was funded by the UK Economic & Social Research Council and was based at the Universities of Oxford and Northumbria.
Airway macrophage metabolic reprogramming during interstitial lung disease
Creators: name: Ogger, Patricia
Publisher: name: Imperial College London
Year: 2020

description: Airway macrophages (AM) play a key role during the pathogenesis of pulmonary fibrosis. The underlying metabolic alterations driving this phenotype however are little understood. The aim of this thesis was to investigate the metabolic phenotype of AMs during pulmonary fibrosis (PF), to identify factors, which influence the pathogenesis of PF and to investigate the role of the immune modulatory metabolite itaconate during PF. In chapter 3, AM metabolic phenotype was analysed in patients with idiopathic pulmonary fibrosis (IPF) or chronic hypersensitivity pneumonitis (CHP) compared to healthy controls. In IPF AMs increased gene expression of first half TCA cycle genes was detected, as well as a dependency on glycolysis to sustain a pro-fibrotic phenotype, while AMs from CHP patients highly increased glycolysis and OXPHOS utilisation and a more pro-inflammatory macrophages phenotype was observed. These results highlight the influence of the environment and identify distinct AM phenotypes in clinically similar IPF and CHP. Recent paradigm shifting studies have shown that two types of AMs exist in the lung and during the pathogenesis of PF. In chapter 4, the underlying metabolic phenotype of tissue-resident (Tr-AM) and monocyte-recruited AMs (Mo-AM) was investigated using the bleomycin mouse model, which showed an increased utilisation of OXPHOS in Tr-AM but not Mo-AM during peak fibrosis. In chapter 5, the role of immune modulatory metabolite itaconate was investigated during PF. Itaconate has been shown to regulate AM metabolic activity and is anti-inflammatory and anti-microbial, however its role in the context of fibrosis is unknown. Analysis of the metabolic phenotype of AMs from IPF patients indicated that there was decreased expression of ACOD1, a gene which controls the synthesis of itaconate. Furthermore, Acod1-/- mice had more severe fibrosis compared to WT mice in bleomycin models, suggesting an anti-fibrotic role for itaconate. Ultimately, fibrosis was ameliorated by treatment with inhaled itaconate or adoptive transfer of itaconate-expressing Mo-AMs. Collectively, these findings reveal underlying metabolic programmes driving AM phenotype during pulmonary fibrosis and identify new therapeutic targets.
Is comprehensive medication review cost-effective for patients admitted to hospital?
Creators: name: Szymanski, Tomasz
Publisher: name: Imperial College London
Year: 2020

description: Problematic polypharmacy is a major public health problem, linked to high morbidity, mortality and use of National Health Service (NHS) resources. Medicines optimisation supports management of polypharmacy, chronic conditions and comorbidities by ensuring appropriate use of medicines. A key component is comprehensive medication review (CMR) – evaluating patients’ medication to optimise use and reduce medication-related problems and waste. CMR is recommended for problematic polypharmacy but its cost-effectiveness in UK hospitals is unknown and uptake is low. This thesis investigates CMR cost-effectiveness in UK NHS hospitals. CMR is complex, with multiple interacting components, and economic evaluation should accommodate the context and complexity. Two de novo cost-effectiveness models were developed, which demonstrated that CMR compared to usual care is a cost-effective use of resources for the general population of elderly acutely hospitalised patients over a short timeframe and for elderly patients with heart failure over a long timeframe. Analysis of data from 3,043 patients in five London hospitals revealed the difference between the number of medicines on discharge and the number of medicines on admission was less with CMR than with usual care. CMR was associated with an increase in the number of medicines deprescribed, held and started. The saving from deprescribing medicines was -£2.78 per month per patient larger in the CMR group than in the usual care group. The results of the empirical study complement the findings from both cost-effectiveness models. Further review and analysis showed that targeting CMR at patients with significant morbidity and mortality, potentially inappropriate prescribing and high treatment costs may increase its health and economic impact. This was exemplified by the cost-effectiveness of CMR for patients with heart failure; the study could be replicated for other diseases. This thesis indicates that well-delivered CMR should be routine hospital care for older patients with co-morbidity and/or specific target conditions.
Local Linear Convergence of the ADMM/Douglas--Rachford Algorithms without Strong Convexity and Application to Statistical Imaging
Creators: name: Aspelmeier, Timo
name: Charitha, C.
name: Luke, D. Russell
Publisher: name: arXiv
Year: 2015
Subjects: subject: Optimization and Control (math.OC)
subject: Numerical Analysis (math.NA)
subject: FOS: Mathematics
subject: 49J52, 49M20, 90C26

description: We consider the problem of minimizing the sum of a convex function and a convex function composed with an injective linear mapping. For such problems, subject to a coercivity condition at fixed points of the corresponding Picard iteration, iterates of the alternating directions method of multipliers converge locally linearly to points from which the solution to the original problem can be computed. Our proof strategy uses duality and strong metric subregularity of the Douglas--Rachford fixed point mapping. Our analysis does not require strong convexity and yields error bounds to the set of model solutions. We show in particular that convex piecewise linear-quadratic functions naturally satisfy the requirements of the theory, guaranteeing eventual linear convergence of both the Douglas--Rachford algorithm and the alternating directions method of multipliers for this class of objectives under mild assumptions on the set of fixed points. We demonstrate this result on quantitative image deconvolution and denoising with multiresolution statistical constraints.
description: Revised manuscript: 30 pages including 9 figures, one appendix and 57 references. Difference from version 2: title and abstract changed, one new figure added, and a posteriori error estimates in numerical experiments reported
(3865) Catherine Cullock/Gordon
Creators: name: Professions, Victorian
Publisher: name: University of Oxford
Year: 2022
Subjects: subject: 220201 Business and Labour History
subject: FOS: Philosophy, ethics and religion
subject: History
subject: 140203 Economic History
subject: FOS: Economics and business

description: This three-year research project began in January 2014 and investigated whether, during the Victorian period, the professions formed a distinct self-sustaining social group with its own mores and values. The project looked at 16,000 individuals drawn from census data for Alnwick, Brighton, Bristol, Dundee, Greenock, Leeds, Merthyr Tydfil, Morpeth, and Winchester. The research project was funded by the UK Economic & Social Research Council and was based at the Universities of Oxford and Northumbria.
title: Investigating the impact of Liverpool accent on language learners’ experiences in a study abroad context
Creators: name: Hope, Kathryn
Publisher: name: University of Liverpool Repository
Year: 2022

description: Accents provide learners of English with an unexpected range of pronunciation in both native and non-native speaker contexts. Few speakers use the standard pronunciation that learners are familiar with. This research project investigates the impact of the wonderfully distinct Liverpool English (LE) accent on English language learners’ listening experiences. Lack of accent familiarity has been identified in previous research as a contributing factor to listening difficulties, yet standard accents continue to be predominant in teaching materials. This thesis assesses the impact of unexpected pronunciation on upper intermediate level learners in a Study Abroad (SA) context. Due to its distinctive features, LE is used as an example to examine how accent may impact students’ communication experiences outside of the class and exam room setting. It investigates the likely sources of problems for learners’ listening in an L2 environment. It explores the quantity and quality of the spoken English that students were exposed to during one-year studying in the UK; the study aimed to understand how learners communicate in the SA experience. This study also investigates how students’ previous ELT experiences prepare them to cope with the realities of listening to language in use. This study uses a mixed methods approach to gather data on students’ initial and ongoing experiences studying and living in the UK. These methods included questionnaires, listening experiences (with rating scales), semi-structured interviews and spoken interaction journals. The findings of this study highlight that accent causes significant listening difficulties for students. Students reported being unable to understand the accents they heard for up to 12 months. Participants stated feeling unprepared and unaware of the vast variety of English accents before they arrived in the UK. Interviews and spoken interaction journals highlighted how these difficulties impacted language use; students spent over half their time communicating in their L1 and reported that LE affected their confidence in using English. These findings indicate that the LE accent is directly impacting students’ ability and confidence communicating with other English speakers. Importantly, it is having an impact on how much English students are able or comfortable to use when they arrive in Liverpool. This study may support the future design and use of listening materials in ELT. This research is likely to contribute to the development of teacher training and learning policies. The conclusions highlight that raising awareness of the variation in English pronunciation and greater exposure to language in use may improve students’ ability and confidence communicating in an L2 environment.
Gamma rays from the Galactic Centre region: a review
Creators: name: van Eldik, Christopher
Publisher: name: arXiv
Year: 2015
Subjects: subject: High Energy Astrophysical Phenomena (astro-ph.HE)
subject: FOS: Physical sciences

description: During the last decades, increasingly precise astronomical observations of the Galactic Centre (GC) region at radio, infrared, and X-ray wavelengths laid the foundations to a detailed understanding of the high energy astroparticle physics of this most remarkable location in the Galaxy. Recently, observations of this region in high energy (HE, 10 MeV - 100GeV) and very high energy (VHE, > 100 GeV) gamma rays added important insights to the emerging picture of the Galactic nucleus as a most violent and active region where acceleration of particles to very high energies -- possibly up to a PeV -- and their transport can be studied in great detail. Moreover, the inner Galaxy is believed to host large concentrations of dark matter (DM), and is therefore one of the prime targets for the indirect search for gamma rays from annihilating or decaying dark matter particles. In this article, the current understanding of the gamma-ray emission emanating from the GC is summarised and the results of recent DM searches in HE and VHE gamma rays are reviewed.
description: invited review, accepted for publication in Astroparticle Physics
The Coordinate Cellular Response to Insulin-like Growth Factor-I (IGF-I) and Insulin-like Growth Factor-binding Protein-2 (IGFBP-2) Is Regulated through Vimentin Binding to Receptor Tyrosine Phosphatase β (RPTPβ)
Creators: name: Xi, Gang
name: Wai, Christine
name: Shen, Xinchun
name: Clemmons, David R.
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2015

description: Insulin-like growth factor-binding protein-2 (IGFBP-2) functions coordinately with IGF-I to stimulate cellular proliferation and differentiation. IGFBP-2 binds to receptor tyrosine phosphatase β (RPTPβ), and this binding in conjunction with IGF-I receptor stimulation induces RPTPβ polymerization leading to phosphatase and tensin homolog inactivation, AKT stimulation, and enhanced cell proliferation. To determine the mechanism by which RPTPβ polymerization is regulated, we analyzed the protein(s) that associated with RPTPβ in response to IGF-I and IGFBP-2 in vascular smooth muscle cells. Proteomic experiments revealed that IGF-I stimulated the intermediate filament protein vimentin to bind to RPTPβ, and knockdown of vimentin resulted in failure of IGFBP-2 and IGF-I to stimulate RPTPβ polymerization. Knockdown of IGFBP-2 or inhibition of IGF-IR tyrosine kinase disrupted vimentin/RPTPβ association. Vimentin binding to RPTPβ was mediated through vimentin serine phosphorylation. The serine threonine kinase PKCζ was recruited to vimentin in response to IGF-I and inhibition of PKCζ activation blocked these signaling events. A cell-permeable peptide that contained the vimentin phosphorylation site disrupted vimentin/RPTPβ association, and IGF-I stimulated RPTPβ polymerization and AKT activation. Integrin-linked kinase recruited PKCζ to SHPS-1-associated vimentin in response to IGF-I and inhibition of integrin-linked kinase/PKCζ association reduced vimentin serine phosphorylation. PKCζ stimulation of vimentin phosphorylation required high glucose and vimentin/RPTPβ-association occurred only during hyperglycemia. Disruption of vimetin/RPTPβ in diabetic mice inhibited RPTPβ polymerization, vimentin serine phosphorylation, and AKT activation in response to IGF-I, whereas nondiabetic mice showed no difference. The induction of vimentin phosphorylation is important for IGFBP-2-mediated enhancement of IGF-I-stimulated proliferation during hyperglycemia, and it coordinates signaling between these two receptor-linked signaling systems.
AITANA-MOMO: Report of dissemination actions
Creators: name: ITI, Instituto Tecnológico de Informática
Publisher: name: Zenodo
Year: 2023
Subjects: AITANAMOMO
2022
artificial intelligence
machine learning
model monitoring
visualization tools
algorithm analysis

description: The use of Artificial Intelligence (AI) and Machine Learning is increasingly present in our daily lives, across all fields and sectors, both industrial and personal. This new revolution, with significant benefits in all areas of our lives, allows us to interact with the devices around us, such as mobile phones or smart home devices, and in the industry, with predictive maintenance mechanisms or digital twins, among many other successful cases of Artificial Intelligence.

AITANA-MoMo project is motivated by the need to control the quality of the models designed by data scientists and MLOps (Machine Learning Operations, a specific DevOps profile for AI) and aims to facilitate the monitoring and maintenance of AI models in production. This is achieved through a set of tools that enable them to identify potential model degradation issues, analyze new datasets, and make the necessary decisions to generate new models that adapt to the new realities of a production environment.

The overall objective of this project is to develop monitoring tools for models in production that facilitate their maintenance and allow for the detection of quality degradation in the models.

This document represents project's dissemination activities.
description: AITANA-MoMo. Project funded by the Valencian Institute of Business Competitiveness (IVACE) and European Union through the European Regional Development Fund (ERDF), within the public grant program adressed to Technological Institutes of the Valencian Community for the development of non-economic R&D projects carried out in cooperation with companies during 2022 with 135.566,10 €. File number: IMDEEA/2022/50
The frail individual: uncovering the complexities in care and support across three common distinct settings.
Creators: name: Sunkersing, David James
Publisher: name: Imperial College London
Year: 2020

description: Introduction By 2050, an estimated 2 billion people will be 65 years or older, bringing significant implications for health and social care. One implication – frailty – will affect patients, staff and healthcare settings. There is a need for improved recognition and care and support of frail individuals. Aims This thesis aims to uncover the complexities in the care and support of frail individuals across three distinct settings. A high-level study investigated the non-acute care setting, followed by investigating three distinct settings: community, acute hospital care and nursing homes. Methods A mixed-methods approach was used. Following a literature review, a survey (questionnaire) helped better understand ‘assessments for frailty’ used in the non-acute care setting. In the community setting, semi-structured interviews were undertaken with patients and healthcare professionals, using a participatory approach. In the acute care setting, a cross-sectional study of frail patients was conducted using patient data records. Regarding nursing homes, an online survey (questionnaire) helped investigate how frailty is assessed. Results Frailty is often understood and assessed as physical and mental health deficits. The perceptions of healthcare professionals and frail individuals regarding frail care and support networks overlap, but are distinct with different emphases. In acute care, variation in frail individuals’ living arrangement pre-admission and post-discharge was found, with a high proportion being discharged to a nursing home. Great variation in assessing for frailty was found in nursing homes. Conclusion Highlighted is the importance of family and friends in the care and support of frail individuals. Many hospital patients were discharged to settings with enhanced care and support availability, demonstrating the importance of care and support. ‘Assessing for frailty’ may require review to ensure holistic consideration of individuals and better frailty recognition. This may help improve the care and support of a frail individual and outcomes.
The MDM2 RING Domain and Central Acidic Domain Play Distinct Roles in MDM2 Protein Homodimerization and MDM2-MDMX Protein Heterodimerization
Creators: name: Zhang, Yanping
name: Ke, Hengming
name: Leslie, Patrick L.
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2015

description: The oncoprotein murine double minute 2 (MDM2) is an E3 ligase that plays a prominent role in p53 suppression by promoting its polyubiquitination and proteasomal degradation. In its active form, MDM2 forms homodimers as well as heterodimers with the homologous protein murine double minute 4 (MDMX), both of which are thought to occur through their respective C-terminal RING (really interesting new gene) domains. In this study, using multiple MDM2 mutants, we show evidence suggesting that MDM2 homo- and heterodimerization occur through distinct mechanisms because MDM2 RING domain mutations that inhibit MDM2 interaction with MDMX do not affect MDM2 interaction with WT MDM2. Intriguingly, deletion of a portion of the MDM2 central acidic domain selectively inhibits interaction with MDM2 while leaving intact the ability of MDM2 to interact with MDMX and to ubiquitinate p53. Further analysis of an MDM2 C-terminal deletion mutant reveals that the C-terminal residues of MDM2 are required for both MDM2 and MDMX interaction. Collectively, our results suggest a model in which MDM2-MDMX heterodimerization requires the extreme C terminus and proper RING domain structure of MDM2, whereas MDM2 homodimerization requires the extreme C terminus and the central acidic domain of MDM2, suggesting that MDM2 homo- and heterodimers utilize distinct MDM2 domains. Our study is the first to report mutations capable of separating MDM2 homo- and heterodimerization.
(3866) John Alexander Sawtell
Creators: name: Professions, Victorian
Publisher: name: University of Oxford
Year: 2022
Subjects: subject: 220201 Business and Labour History
subject: FOS: Philosophy, ethics and religion
subject: History
subject: 140203 Economic History
subject: FOS: Economics and business

description: This three-year research project began in January 2014 and investigated whether, during the Victorian period, the professions formed a distinct self-sustaining social group with its own mores and values. The project looked at 16,000 individuals drawn from census data for Alnwick, Brighton, Bristol, Dundee, Greenock, Leeds, Merthyr Tydfil, Morpeth, and Winchester. The research project was funded by the UK Economic & Social Research Council and was based at the Universities of Oxford and Northumbria.
Compartmental arthroplasty in the treatment of osteoarthritis of the knee
Creators: name: Garner, Amy J.
Publisher: name: Imperial College London
Year: 2021

description: INTRODUCTION: Compartmental Arthroplasty: ipsilateral combinations of partial knee arthroplasty (CPKA), are Anterior Cruciate Ligament (ACL) preserving alternatives to Total Knee Arthroplasty (TKA) in the treatment of osteoarthritis. This thesis investigates the biomechanics, gait characteristics and patient reported outcomes of CPKA. METHODS: In vitro, the extensor moment, relative implant efficiency and anterior-posterior stability, of cadaveric specimens were determined with varying implant combinations in situ. CPKA subjects were measured on an instrumented treadmill at top walking speeds, then compared to matched healthy and primary posterior-cruciate retaining TKA subjects using the vertical component of ground reaction forces and temporospatial measurements. Finally, satisfaction was determined using the Oxford Knee Score and quality of life was assessed using the EuroQol-5D. RESULTS: In vitro, UKA and CPKA generated the same extensor moment as native knees at low flexion angles, where TKA were less efficient. In deep flexion, the extensor mechanism was marginally more efficient following TKA than CPKA. Overall efficiency of UKA and CPKA were near-normal but significantly reduced following TKA. UKA and BCA demonstrated normal anterior-posterior stability, whilst Bi-UKA demonstrated increased anterior laxity. TKA were least anterior-posterior stable at all flexion angles. In the gait lab, CPKA subjects recorded faster speeds than TKA counterparts, near-normal weight-acceptance, maximum weight-acceptance force and mid-stance forces. CPKA had longer step and stride lengths, and reported higher OKS and EQ-5D scores. DISCUSSION: CPKA may be utilised in primary two-compartment disease or for native compartment degeneration in a knee with an existing partial knee implant, through the addition of a partial knee arthroplasty. Conservation of the ACL, healthy bone and peri-articular tissue during CPKA preserves near-native extensor efficiency, anterior-posterior stability, highly functional fast walking, good patient satisfaction and quality of life. CONCLUSIONS: Emerging evidence suggests that CPKA may be a high-functioning, satisfying alternative to TKA in patients with multi-compartment osteoarthritis.
The SP theory of intelligence: distinctive features and advantages
Creators: name: Wolff, J. G.
Publisher: name: arXiv
Year: 2015
Subjects: subject: Artificial Intelligence (cs.AI)
subject: FOS: Computer and information sciences

description: This paper highlights distinctive features of the "SP theory of intelligence" and its apparent advantages compared with some AI-related alternatives. Distinctive features and advantages are: simplification and integration of observations and concepts; simplification and integration of structures and processes in computing systems; the theory is itself a theory of computing; it can be the basis for new architectures for computers; information compression via the matching and unification of patterns and, more specifically, via multiple alignment, is fundamental; transparency in the representation and processing of knowledge; the discovery of 'natural' structures via information compression (DONSVIC); interpretations of mathematics; interpretations in human perception and cognition; and realisation of abstract concepts in terms of neurons and their inter-connections ("SP-neural"). These things relate to AI-related alternatives: minimum length encoding and related concepts; deep learning in neural networks; unified theories of cognition and related research; universal search; Bayesian networks and more; pattern recognition and vision; the analysis, production, and translation of natural language; Unsupervised learning of natural language; exact and inexact forms of reasoning; representation and processing of diverse forms of knowledge; IBM's Watson; software engineering; solving problems associated with big data, and in the development of intelligence in autonomous robots. In conclusion, the SP system can provide a firm foundation for the long-term development of AI, with many potential benefits and applications. It may also deliver useful results on relatively short timescales. A high-parallel, open-source version of the SP machine, derived from the SP computer model, would be a means for researchers everywhere to explore what can be done with the system, and to create new versions of it.
Adding value to outpatient heart failure services and the patient journey through digital transformation of services
Creators: name: Singhal, Arvind
Publisher: name: Imperial College London
Year: 2022

description: Introduction Heart failure (HF) is a chronic condition affecting over 900,000 people in the UK. The management of patients with HF frequently involves regular face-to-face appointments. Digital transformation of care with telemedicine, remote monitoring and mobile applications (Apps) may help improve patient experience and relieve demand on services. The Covid-19 pandemic resulted in an acceleration in telemedicine. This thesis evaluates pre-pandemic HF services at the Royal Brompton Hospital (RBH), identifying potential areas for improving patient journeys. Methods Retrospective cohort studies including over 200 patients were used to analyse the activities and actions resulting from HF clinic appointments over 3 years. Time-and-motion studies were conducted for each of the 4 consultant-led HF clinics at RBH, where flow through hospital was analysed for 58 patients. Eight clinicians and 8 patients who had undergone telemedicine consultations were interviewed about their experiences and perceptions, with narrative data thematically analysed. Focus groups and existing educational material were used to design an educational App for HF. Results Most HF patients under long-term follow-up were followed up twice yearly. At clinic visit, worsening HF symptoms and therapy change by clinicians were uncommon (21% and 36% of appointments respectively). Patients spent a median of 103 minutes in hospital on the day of an appointment for a median 20-minute consultation. The majority of consultations ran late. Clinicians and patients found telemedicine consultations generally acceptable, but both groups identified changes in time utilisation, clinical assessment, communication, and technology. Telemedicine appointments were shorter and involved less time waiting and travelling for patients. Patients and clinicians agreed that when patients are “stable”, telemedicine is preferred. A prototype HF educational “Avatar”-based App was produced. Conclusion Digital transformation of outpatient services, including telemedicine can improve patient and clinician experience, efficiency and rationalise limited resources, thus adding value to outpatient HF care.
Evaluation of strategies for reducing the burden of COPD in the UK using Bayesian methods
Creators: name: Adamson, Alex James
Publisher: name: Imperial College London
Year: 2022

description: Chronic obstructive pulmonary disease (COPD) is responsible for 5.3% of all deaths and 1.7% of all hospital admissions in the UK. This thesis focuses on strategies to reduce COPD burden by targeting three aspects across the public healthcare system: prevention, emergency treatment, and long-term management. Analyses were performed in a Bayesian framework to exploit its flexibility in modelling uncertainty and the incorporation of prior knowledge. First, I assessed whether communication of personalised disease risk in primary care is an effective smoking cessation intervention, using cost-effectiveness and value of information analyses based on various data sources across the literature. The odds ratio for the effectiveness of communication of personalised disease risk was 1.48 (95%CrI:0.91-2.26). While I found a probability of cost-effectiveness of about 90%, further research up to a maximum of £27 million is justified to reduce the uncertainty around this estimate. Secondly, I assessed whether case ascertainment affects the detection of poorly performing hospital trusts in the treatment of acute exacerbation of COPD (AECOPD) in secondary care, using data from the National Asthma and COPD Audit Programme. Case ascertainment was associated with 30-day mortality (OR:1.74; 1.25-2.41) and adjusting for it impacted the findings, with 5 trusts becoming outliers and 2 trusts no longer classified as outliers. Finally, using general practice data from Clinical Practice Research Datalink, I assessed whether new guidelines suggesting triple therapy (long-acting beta-2 agonists, LABA + long-acting muscarinic antagonists, LAMA + inhaled corticosteroids, ICS) for the treatment of those with poorly-controlled COPD on LABA+LAMA dual therapy improves disease outcomes. Triple therapy was not associated with severe AECOPD (IRR:1.00; 0.93-1.07) or mortality (IRR:0.95; 0.86-1.06), but was associated with increased risk of pneumonia (IRR:1.19; 1.05-1.35). This thesis applied sophisticated Bayesian methods to increase understanding of how COPD burden could be reduced in different areas of the public healthcare system.
(3862) Janet Jessie Mann Sutherland
Creators: name: Professions, Victorian
Publisher: name: University of Oxford
Year: 2022
Subjects: subject: 220201 Business and Labour History
subject: FOS: Philosophy, ethics and religion
subject: History
subject: 140203 Economic History
subject: FOS: Economics and business

description: This three-year research project began in January 2014 and investigated whether, during the Victorian period, the professions formed a distinct self-sustaining social group with its own mores and values. The project looked at 16,000 individuals drawn from census data for Alnwick, Brighton, Bristol, Dundee, Greenock, Leeds, Merthyr Tydfil, Morpeth, and Winchester. The research project was funded by the UK Economic & Social Research Council and was based at the Universities of Oxford and Northumbria.
Dissecting the role of Aryl Hydrocarbon Receptor in adipose and vascular homeostasis
Creators: name: Burke, Alice Louise
Publisher: name: Imperial College London
Year: 2022

description: Aryl Hydrocarbon Receptor (AHR) is a ligand activated transcription factor, which was initially characterised as an environmental sensor, that mediates toxic effects in response to harmful chemicals. Early research therefore focussed on exogenous ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which elicit a sustained activation of the AHR pathway, rather than a transient one associated with natural ligands. More recently, AHR has been implicated in obesity. The incidence of obesity has increased dramatically over recent decades, and carries a high burden to health care systems, along with increased prevalence of cardiovascular disease and cancer. Continued work surrounding obesity has shown that thermogenesis contributes to energy balance, and is now an attractive therapeutic target to attempt to reduce obesity rates. Findings show that AHR is not required for activation, nor regulation of thermogenesis through the characterisation of the global AHR knock out (KO) and adipocyte-specific AHR KO mouse models when exposed to cold. Both AHR KO and adipocyte-specific KO animals are able to maintain body temperature when exposed to acute cold challenge. No differences were observed in oxygen consumption nor energy expenditure. These mice were also able to maintain body temperature upon fasting prior to cold exposure. Endothelial cells (ECs) were also selected as an important cell-type to investigate AHR function due to the severe vascular defects of global AHR KO animals. Vascular disease is again associated with a high burden on healthcare, especially in the ageing population and in individuals who are obese. A human model system of human umbilical vein endothelial cells (HUVECs) was used to investigate novel functions of AHR in ECs in vitro. Bulk RNA sequencing revealed that AHR activation caused a downregulation of many cell cycle-related pathways. Functional data using EdU staining also verified that activation of AHR with various concentrations of FICZ for 6Hrs caused a transient accumulation of cells in G0/1, whilst S and G2/M remained unchanged when compared to DMSO control. Further protein expression analysis at a single cell resolution using Operetta indicated that these effects were mediated through E2F. In addition, AHR was knocked down in HUVECs, which saw a decrease in cells at G1/0 compared to control siKD cells, and an increase in S phase when stained with EdU. Cells reached confluency more rapidly in siAHR group, compared to siKD control group using Incucyte. Increases in E2F were also observed using the Operetta system.
Investigations of the coordinates in Ptolemy's Geographike Hyphegesis Book 8
Creators: name: Marx, Christian
Publisher: name: arXiv
Year: 2015
Subjects: subject: History and Philosophy of Physics (physics.hist-ph)
subject: FOS: Physical sciences
subject: 01A20

description: In Book 8 of his Geographike Hyphegesis Ptolemy gives coordinates for ca. 360 so-called noteworthy cities. These coordinates are the time difference to Alexandria, the length of the longest day, and partly the ecliptic distance from the summer solstice. The supposable original conversions between the coordinates in Book 8 and the geographical coordinates in the location catalogue of Books 2-7 including the underlying parameters and tabulations are here reconstructed. The results document the differences between the $Ω$- and $Ξ$-recension. The known difference in the longitude of Alexandria underlying the conversion of the longitudes is examined more closely. For the ecliptic distances from the summer solstice of the $Ω$-recension it is revealed that they were originally computed by means of a so far undiscovered approximate, linear conversion. Further it is shown that the lengths of the longest day could be based on a linear interpolation of the data in the Mathematike Syntaxis 2.6.
description: 28 pages, 11 figures; author generated postprint; the final publication is available at Springer via http://dx.doi.org/10.1007/s00407-012-0102-0
Transmission of Atherosclerosis Susceptibility with Gut Microbial Transplantation
Creators: name: Zhu, Weifei
name: Buffa, Jennifer A.
name: Org, Elin
name: Bennett, Brian J.
name: DiDonato, Joseph A.
name: Lusis, Aldons J.
name: Hazen, Stanley L.
name: Gregory, Jill C.
name: Wagner, Matthew A.
name: Levison, Bruce S.
name: Li, Lin
name: Wang, Zeneng
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2015

description: Recent studies indicate both clinical and mechanistic links between atherosclerotic heart disease and intestinal microbial metabolism of certain dietary nutrients producing trimethylamine N-oxide (TMAO). Here we test the hypothesis that gut microbial transplantation can transmit choline diet-induced TMAO production and atherosclerosis susceptibility. First, a strong association was noted between atherosclerotic plaque and plasma TMAO levels in a mouse diversity panel (n = 22 strains, r = 0.38; p = 0.0001). An atherosclerosis-prone and high TMAO-producing strain, C57BL/6J, and an atherosclerosis-resistant and low TMAO-producing strain, NZW/LacJ, were selected as donors for cecal microbial transplantation into apolipoprotein e null mice in which resident intestinal microbes were first suppressed with antibiotics. Trimethylamine (TMA) and TMAO levels were initially higher in recipients on choline diet that received cecal microbes from C57BL/6J inbred mice; however, durability of choline diet-dependent differences in TMA/TMAO levels was not maintained to the end of the study. Mice receiving C57BL/6J cecal microbes demonstrated choline diet-dependent enhancement in atherosclerotic plaque burden as compared with recipients of NZW/LacJ microbes. Microbial DNA analyses in feces and cecum revealed transplantation of donor microbial community features into recipients with differences in taxa proportions between donor strains that were transmissible to recipients and that tended to show coincident proportions with TMAO levels. Proportions of specific taxa were also identified that correlated with plasma TMAO levels in donors and recipients and with atherosclerotic lesion area in recipients. Atherosclerosis susceptibility may be transmitted via transplantation of gut microbiota. Gut microbes may thus represent a novel therapeutic target for modulating atherosclerosis susceptibility.