• UK-India Centre for Advanced Technology for Minimizing Indiscriminate Use of Antibiotics:"Exploring biology of antibiotic resistance and potential targets for early diagnosis and effective management of infectious diseases”

      Rimmer, Stephen; Garg, P.; MacNeil, S.; Shepherd, J.; Foster, S. (2017-05)
      During January 15th – 17th, 2017 a group of scientists met, under the auspices of the UK-India Centre for Advanced Technology for Minimizing Indiscriminate Use of Antibiotics, to discuss the further developments and potential solutions to antimicrobial resistance. This was the third work shop under this funding stream held in Hyderabad. The presentations and outcomes of the workshop are released here. Key out comes included the need to address improved treatment and detection of TB, delivery of antimicrobial peptides, potential strategies for combating beta-lactam resistance.
    • Ultrasmall SnO(2) nanocrystals: hot-bubbling synthesis, encapsulation in carbon layers and applications in high capacity Li-ion storage

      Ding, L.; He, S.; Miao, S.; Jorgensen, M.R.; Leubner, S.; Yan, C.; Hickey, Stephen G.; Eychmüller, A.; Xu, J.; Schmidt, O.G. (2014-04-15)
      Ultrasmall SnO2 nanocrystals as anode materials for lithium-ion batteries (LIBs) have been synthesized by bubbling an oxidizing gas into hot surfactant solutions containing Sn-oleate complexes. Annealing of the particles in N2 carbonifies the densely packed surface capping ligands resulting in carbon encapsulated SnO2 nanoparticles (SnO2/C). Carbon encapsulation can effectively buffer the volume changes during the lithiation/delithiation process. The assembled SnO2/C thus deliver extraordinarily high reversible capacity of 908 mA.h.g(-1) at 0.5 C as well as excellent cycling performance in the LIBs. This method demonstrates the great potential of SnO2/C nanoparticles for the design of high power LIBs.
    • Ultrasound-triggered therapeutic microbubbles enhance the efficacy of cytotoxic drugs by increasing circulation and tumour drug accumulation and limiting bioavailability and toxicity in normal tissues

      Ingram, N.; McVeigh, L.E.; Abou-Saleh, R.H.; Maynard, J.; Peyman, S.A.; McLaughlan, J.R.; Fairclough, M.; Marston, G.; Valleley, E.M.A.; Jimenez-Macias, J.L.; et al. (2020)
      Most cancer patients receive chemotherapy at some stage of their treatment which makes improving the efficacy of cytotoxic drugs an ongoing and important goal. Despite large numbers of potent anti-cancer agents being developed, a major obstacle to clinical translation remains the inability to deliver therapeutic doses to a tumor without causing intolerable side effects. To address this problem, there has been intense interest in nanoformulations and targeted delivery to improve cancer outcomes. The aim of this work was to demonstrate how vascular endothelial growth factor receptor 2 (VEGFR2)-targeted, ultrasound-triggered delivery with therapeutic microbubbles (thMBs) could improve the therapeutic range of cytotoxic drugs. Methods: Using a microfluidic microbubble production platform, we generated thMBs comprising VEGFR2-targeted microbubbles with attached liposomal payloads for localised ultrasound-triggered delivery of irinotecan and SN38 in mouse models of colorectal cancer. Intravenous injection into tumor-bearing mice was used to examine targeting efficiency and tumor pharmacodynamics. High-frequency ultrasound and bioluminescent imaging were used to visualise microbubbles in real-time. Tandem mass spectrometry (LC-MS/MS) was used to quantitate intratumoral drug delivery and tissue biodistribution. Finally, 89Zr PET radiotracing was used to compare biodistribution and tumor accumulation of ultrasound-triggered SN38 thMBs with VEGFR2 targeted SN38 liposomes alone. Results: ThMBs specifically bound VEGFR2 in vitro and significantly improved tumor responses to low dose irinotecan and SN38 in human colorectal cancer xenografts. An ultrasound trigger was essential to achieve the selective effects of thMBs as without it, thMBs failed to extend intratumoral drug delivery or demonstrate enhanced tumor responses. Sensitive LC-MS/MS quantification of drugs and their metabolites demonstrated that thMBs extended drug exposure in tumors but limited exposure in healthy tissues, not exposed to ultrasound, by persistent encapsulation of drug prior to elimination. 89Zr PET radiotracing showed that the percentage injected dose in tumors achieved with thMBs was twice that of VEGFR2-targeted SN38 liposomes alone. Conclusions: thMBs provide a generic platform for the targeted, ultrasound-triggered delivery of cytotoxic drugs by enhancing tumor responses to low dose drug delivery via combined effects on circulation, tumor drug accumulation and exposure and altered metabolism in normal tissues.
    • Ultraviolet-radiation induced skin inflammation: dissecting the role of bioactive lipids

      Pilkington, S.M.; Rhodes, L.E.; Nicolaou, Anna (2011)
      Acute exposure of human skin to the ultraviolet radiation (UVR) in sunlight results in the sunburn response. This is mediated in part by pro-inflammatory eicosanoids and other bioactive lipids, which are in turn produced via mechanisms including UVR-induction of oxidative stress, cell signalling and gene expression. Sunburn is a self-limiting inflammation offering a convenient and accessible system for the study of human cutaneous lipid metabolism. Recent lipidomic applications have revealed that a wider diversity of eicosanoids may be involved in the sunburn response than previously appreciated. This article reviews the effects of UVR on cutaneous lipids and examines the contribution of bioactive lipid mediators in the development of sunburn. Since human skin is an active site of polyunsaturated fatty acid (PUFA) metabolism, and these macronutrients can influence the production of eicosanoids/bioactive lipids, as well as modulate cell signalling, gene expression and oxidative stress, the application of PUFA as potential photoprotective agents is also considered.
    • Unaltered perception of suprathreshold contrast in early glaucoma despite sensitivity loss

      Bham, H.A.; Dewsbery, S.D.; Denniss, Jonathan (2020-07)
      PURPOSE. Glaucoma raises contrast detection thresholds, but our natural visual environment is dominated by high contrast that may remain suprathreshold in early to moderate glaucoma. This study investigates the effect of glaucoma on the apparent contrast of visible stimuli. METHODS. Twenty participants with glaucoma with partial visual field defects (mean age, 72 ± 7 years) and 20 age-similar healthy controls (mean age, 70 ± 7 years) took part. Contrast detection thresholds for Gabor stimuli (SD, 0.75°) of four spatial frequencies (0.5, 1.0, 2.0, and 4.0 c/deg) were first measured at 10° eccentricity, both within and outside of visual field defects for participants with glaucoma. Subsequently, the contrast of a central Gabor was matched to that of a peripheral Gabor with contrast fixed at two times or four times the detection threshold. Data were analyzed by linear mixed modelling. RESULTS. Compared with controls, detection thresholds for participants with glaucoma were raised by 0.05 ± 0.025 (Michelson units, ± SE; P = 0.12) and by 0.141 ± 0.026 (P < 0.001) outside and within visual field defects, respectively. For reference stimuli at two times the detection contrast, matched contrast ratios (matched/reference contrast) were 0.16 ± 0.039 (P < 0.001) higher outside compared with within visual field defects in participants with glaucoma. Matched contrast ratios within visual field defects were similar to controls (mean 0.033 ± 0.066 lower; P = 0.87). For reference stimuli at four times the detection contrast, matched contrast ratios were similar across all three groups (P = 0.58). Spatial frequency had a minimal effect on matched contrast ratios. CONCLUSIONS. Despite decreased contrast sensitivity, people with glaucoma perceive the contrast of visible suprathreshold stimuli similarly to healthy controls. These results suggest possible compensation for sensitivity loss in the visual system.
    • Uncovering Molecular Processes in Crystal Nucleation and Growth by Using Molecular Simulation

      Anwar, Jamshed; Zahn, D. (27/01/2011)
      Exploring nucleation processes by molecular simulation can provide a mechanistic understanding at the atomic level and also enables kinetic and thermodynamic quantities to be estimated. However, whilst the potential for modeling crystal nucleation and growth processes is immense, there are specific technical challenges to modeling [that need to be tackled]. In general, rare events, such as nucleation cannot be simulated using a direct ¿brute force¿ molecular dynamics approach. In recent years, the limited time and length scales that are accessible by conventional molecular dynamics simulations have inspired a number of advances to tackle problems that were hitherto considered outside the scope of molecular simulation. While general insights and features could be explored from efficient generic models, The newer methods have paved the way to realistic crystal nucleation scenarios. The association of single ions in solvent environments, the mechanisms of motif formation in solvents, the nucleation process itself, ripening reactions, role of additives, as well as the self-organization of nanocrystals can now all be investigated at the molecular level. The insights gained should complement experiments and enhance our fundamental understanding of the processes involved and facilitate the rational design of new materials.
    • Understanding images in biological and computer vision

      Schofield, A.J.; Gilchrist, I.D.; Bloj, Marina; Leonardis, A.; Bellotto, N. (2018-06-15)
      This issue of Interface Focus is a collection of papers arising out of a Royal Society Discussion meeting entitled ‘Understanding images in biological and computer vision’ held at Carlton Terrace on the 19th and 20th February, 2018. There is a strong tradition of inter-disciplinarity in the study of visual perception and visual cognition. Many of the great natural scientists including Newton [1], Young [2] and Maxwell (see [3]) were intrigued by the relationship between light, surfaces and perceived colour considering both physical and perceptual processes. Brewster [4] invented both the lenticular stereoscope and the binocular camera but also studied the perception of shape-from-shading. More recently, Marr's [5] description of visual perception as an information processing problem led to great advances in our understanding of both biological and computer vision: both the computer vision and biological vision communities have a Marr medal. The recent successes of deep neural networks in classifying the images that we see and the fMRI images that reveal the activity in our brains during the act of seeing are both intriguing. The links between machine vision systems and biology may at sometimes be weak but the similarity of some of the operations is nonetheless striking [6]. This two-day meeting brought together researchers from the fields of biological and computer vision, robotics, neuroscience, computer science and psychology to discuss the most recent developments in the field. The meeting was divided into four themes: vision for action, visual appearance, vision for recognition and machine learning.
    • Understanding long-term opioid prescribing for non-cancer pain in primary care: A qualitative study

      McCrorie, C.; Closs, S.J.; House, A.; Petty, Duncan R.; Ziegler, L.; Glidewell, L.; West, R.; Foy, R. (2015-09)
      Background: The place of opioids in the management of chronic, non-cancer pain is limited. Even so their use is escalating, leading to concerns that patients are prescribed strong opioids inappropriately and alternatives to medication are under-used. We aimed to understand the processes which bring about and perpetuate long-term prescribing of opioids for chronic, non-cancer pain. Methods: We held semi-structured interviews with patients and focus groups with general practitioners (GPs). Participants included 23 patients currently prescribed long-term opioids and 15 GPs from Leeds and Bradford, United Kingdom (UK). We used a grounded approach to the analysis of transcripts. Results: Patients are driven by the needs for pain relief, explanation, and improvement or maintenance of quality of life. GPs’ responses are shaped by how UK general practice is organised, available therapeutic choices and their expertise in managing chronic pain, especially when facing diagnostic uncertainty or when their own approach is at odds with the patient’s wishes. Four features of the resulting transaction between patients and doctors influence prescribing: lack of clarity of strategy, including the risk of any plans being subverted by urgent demands; lack of certainty about locus of control in decision-making, especially in relation to prescribing; continuity in the doctor-patient relationship; and mutuality and trust. Conclusions: Problematic prescribing occurs when patients experience repeated consultations that do not meet their needs and GPs feel unable to negotiate alternative approaches to treatment. Therapeutic short-termism is perpetuated by inconsistent clinical encounters and the absence of mutually-agreed formulations of underlying problems and plans of action. Apart from commissioning improved access to appropriate specialist services, general practices should also consider how they manage problematic opioid prescribing and be prepared to set boundaries with patients.
    • Understanding the economic influence of the dyeing industry in Pompeii through the application of experimental archaeology and thermodynamics

      Hopkins, Heather J.; Willimott, L.; Janaway, Robert C.; Robinson, Damian; Seale, W.J. (2005)
      The influence of the dyeing industry in Pompeii on the local economy has been under discussion since the publication by Moeller in 1976. Since no absolute answer has emerged, the question was re-examined using two additional methods, experimental archaeology and the principles of thermodynamics. A full-scale replica of a dyeing apparatus from Pompeii was constructed and used to simulate repeated dye runs, and so determine operating parameters such as the times involved to heat and cool a vat and the consumables needed. This first replica also allowed a better understanding of how the apparatus was actually used. Thermodynamic principles, which were applied to understand the successes and failures within the experimental work, suggested that the vat operated in a predictable way and enabled the operational mechanics of the vat to be established. It is now possible to use both the experimental results and the thermodynamic modelling to determine not just the consumables used, but also the working environment needed for the vat to operate, allowing an understanding of the limitations to dyeing and to workers. Issues of practicality such as storage of consumables and disposal of exhaust gases may now be thoroughly examined. 2 Eventually it will be possible to determine the operating parameters of each of the dye vats, the quantities of consumables involved and the amount that could be produced. This should help answer the question as to the significance of the dye industry in Pompeii to the local economy.
    • Understanding the neural basis of amblyopia.

      Barrett, Brendan T.; Bradley, A.; McGraw, Paul V. (2004)
      Amblyopia is the condition in which reduced visual function exists despite full optical correction and an absence of observable ocular pathology. Investigation of the underlying neurology of this condition began in earnest around 40 years ago with the pioneering studies conducted by Hubel and Wiesel. Their early work on the impact of monocular deprivation and strabismus initiated what is now a rapidly developing field of cortical plasticity research. Although the monocular deprivation paradigm originated by Hubel and Wiesel remains a key experimental manipulation in studies of cortical plasticity, somewhat ironically, the neurology underlying the human conditions of strabismus and amblyopia that motivated this early work remains elusive. In this review, the authors combine contemporary research on plasticity and development with data from human and animal investigations of amblyopic populations to assess what is known and to reexamine some of the key assumptions about human amblyopia.
    • Understanding the quorum-sensing bacterium Pantoea stewartii strain M009 with whole-genome sequencing analysis

      Tan, W.; Chang, Chien-Yi; Yin, W.; Chan, K. (2015-01)
      Pantoea stewartii is known to be the causative agent of Stewart's wilt, which usually affects sweet corn (Zea mays) with the corn flea beetle as the transmission vector. In this work, we present the whole-genome sequence of Pantoea stewartii strain M009, isolated from a Malaysian tropical rainforest waterfall.
    • Undertaking sex assessment

      Brickley, M.; Buckberry, Jo (CIFA, 2018)
    • Unexpected high prevalence of resistance-associated Rv0678 variants in MDR-TB patients without documented prior use of clofazimine or bedaquiline.

      Villellas, C.; Coeck, N.; Meehan, Conor J.; Lounis, N.; de Jong, B.; Rigouts, L.; Andries, K. (2017-03)
      Objectives: Resistance-associated variants (RAVs) in Rv0678, a regulator of the MmpS5-MmpL5 efflux pump, have been shown to lead to increased MICs of bedaquiline (2- to 8- fold) and clofazimine (2- to 4-fold). The prevalence of these Rv0678 RAVs in clinical isolates and their impact on treatment outcomes are important factors to take into account in bedaquiline treatment guidelines. Methods: Baseline isolates from two bedaquiline MDR-TB clinical trials were sequenced for Rv0678 RAVs and corresponding bedaquiline MICs were determined on 7H11 agar. Rv0678 RAVs were also investigated in non-MDRTB sequences of a population-based cohort. Results: Rv0678 RAVs were identified in 23/347 (6.3%) of MDR-TB baseline isolates. Surprisingly, bedaquiline MICs for these isolates were high (>0.24 mg/L, n¼8), normal (0.03 0.24 mg/L, n¼11) or low(<0.03 mg/L, n¼4). A variant at position 11 in the intergenic region mmpS5–Rv0678 was identified in 39 isolates (11.3%) and appeared to increase the susceptibility to bedaquiline. In non-MDR-TB isolates, the frequency of Rv0678 RAVs was lower (6/ 852 or 0.7%). Competition experiments suggested that rifampicin was not the drug selecting for Rv0678 RAVs. Conclusions: RAVs in Rv0678 occur more frequently in MDR-TB patients than previously anticipated, are not associated with prior use of bedaquiline or clofazimine, and in the majority of cases do not lead to bedaquiline MICs above the provisional breakpoint (0.24mg/L). Their origin remains unknown. Given the variety of RAVs in Rv0678 and their variable effects on the MIC, only phenotypic drug-susceptibility methods can currently be used to assess bedaquiline susceptibility.
    • A unifying hypothesis for control of body weight and reproduction in seasonally breeding mammals

      Helfer, Gisela; Barrett, P.; Morgan, P.J. (2019-03)
      Animals have evolved diverse seasonal variations in physiology and reproduction to accommodate yearly changes in environmental and climatic conditions. These changes in physiology are initiated by changes in photoperiod (daylength) and are mediated through melatonin, which relays photoperiodic information to the pars tuberalis of the pituitary gland. Melatonin drives thyroid‐stimulating hormone transcription and synthesis in the pars tuberalis, which, in turn, regulates thyroid hormone and retinoic acid synthesis in the tanycytes lining the third ventricle of the hypothalamus. Seasonal variation in central thyroid hormone signalling is conserved among photoperiodic animals. Despite this, different species adopt divergent phenotypes to cope with the same seasonal changes. A common response amongst different species is increased hypothalamic cell proliferation/neurogenesis in short photoperiod. That cell proliferation/neurogenesis may be important for seasonal timing is based on (i) the neurogenic potential of tanycytes; (ii) the fact that they are the locus of striking seasonal morphological changes; and (iii) the similarities to mechanisms involved in de novo neurogenesis of energy balance neurones. We propose that a decrease in hypothalamic thyroid hormone and retinoic acid signalling initiates localised neurodegeneration and apoptosis, which leads to a reduction in appetite and body weight. Neurodegeneration induces compensatory cell proliferation from the neurogenic niche in tanycytes and new cells are born under short photoperiod. Because these cells have the potential to differentiate into a number of different neuronal phenotypes, this could provide a mechanistic basis to explain the seasonal regulation of energy balance, as well as reproduction. This cycle can be achieved without changes in thyroid hormone/retinoic acid and explains recent data obtained from seasonal animals held in natural conditions. However, thyroid/retinoic acid signalling is required to synchronise the cycles of apoptosis, proliferation and differentiation. Thus, hypothalamic neurogenesis provides a framework to explain diverse photoperiodic responses.
    • United Kingdom: Brief overview of the health supply chain in the country

      Breen, Liz; Urban, Rachel L.; Zaman, Hadar (2018)
      The health supply chain within the United Kingdom follows a traditional model adopted by many countries globally. This is typically the sourcing of products from manufacturer to pharmacy (hospital and community) via wholesaler or direct. New models of delivery are being piloted and evaluated to improve supply chain efficiency and effectiveness
    • Unveiling the prehistoric landscape at Stonehenge through multi-receiver EMI

      De Smedt, P; Van Meirvenne, M.; Saey, T.; Baldwin, E.; Gaffney, Christopher F.; Gaffney, Vincent L. (2014-10)
      Archaeological research at Stonehenge (UK) is increasingly aimed at understanding the dynamic of the wider archaeological landscape. Through the application of state-of-the-art geophysical techniques, unprecedented insight is being gathered into the buried archaeological features of the area. However, applied survey techniques have rarely targeted natural soil variation, and the detailed knowledge of the palaeotopography is consequently less complete. In addition, metallic topsoil debris, scattered over different parts of the Stonehenge landscape, often impacts the interpretation of geophysical datasets. The research presented here demonstrates how a single multi-receiver electromagnetic induction (EMI) survey, conducted over a 22 ha area within the Stonehenge landscape, offers detailed insight into natural and anthropogenic soil variation at Stonehenge. The soil variations that were detected through recording the electrical and magnetic soil variability, shed light on the genesis of the landscape, and allow for a better definition of potential palaeoenvironmental and archaeological sampling locations. Based on the multi-layered dataset, a procedure was developed to remove the influence of topsoil metal from the survey data, which enabled a more straightforward identification of the detected archaeology. The results provide a robust basis for further geoarchaeological research, while potential to differentiate between modern soil disturbances and the underlying sub-surface variations can help in solving conservation and management issues. Through expanding this approach over the wider area, we aim at a fuller understanding of the human–landscape interactions that have shaped the Stonehenge landscape.
    • An update on genomic-guided therapies for pediatric solid tumors

      Tsui, P.C.; Lee, Stephanie; Liu, Z.W.Y.; Ip, L.R.H.; Piao, W.; Chiang, A.K.S.; Lui, V.W.Y. (2017-06)
      Currently, out of the 82 US FDA-approved targeted therapies for adult cancer treatments, only three are approved for use in children irrespective of their genomic status. Apart from leukemia, only a handful of genomic-based trials involving children with solid tumors are ongoing. Emerging genomic data for pediatric solid tumors may facilitate the development of precision medicine in pediatric patients. Here, we provide an up-to-date review of all reported genomic aberrations in the eight most common pediatric solid tumors with whole-exome sequencing or whole-genome sequencing data (from cBioPortal database, Pediatric Cancer Genome Project, Therapeutically Applicable Research to Generate Effective Treatments) and additional non-whole-exome sequencing studies. Potential druggable events are highlighted and discussed so as to facilitate preclinical and clinical research in this area.
    • Uptake of oral anticoagulants for stroke prevention in patients with atrial fibrillation in a single Clinical Commissioning Group in England without restrictions to their use

      Medlinskiene, Kristina; Fay, M.; Petty, Duncan R. (2019-04)
      Background and Objective In England, the uptake of direct oral anticoagulants (DOACs) for stroke prevention in atrial fbrillation has been slow and varied across diferent Clinical Commissioning Groups (CCGs). This study aimed to profle the prescribing of oral anticoagulants for stroke prevention in patients with atrial fbrillation over 3 years in a CCG without restrictions to DOACs use to understand more about organisational and/or individual barriers to the early uptake of DOACs. Methods Data were collected from nine general practices between 1 April 2012 and 31 March 2015 of patients who were initiated on the oral anticoagulant therapy. Data were analysed descriptively and with independent Student’s t test and Chi square test to explore if there was an association between type of oral anticoagulant initiated and sex, age, type of prescriber and prior aspirin use. Results The early uptake of DOACs signifcantly increased over the study period (p<0.0001; medium size efect φc=0.372). There was no statistically signifcant diference between sex or age and type of oral anticoagulant initiated. Primary-care prescribers were responsible for initiating the majority of oral anticoagulants (71%; N=257) and driving the use of DOACs (72%, N=71). Patients switched from aspirin to an oral anticoagulant were more likely to be initiated on warfarin than a DOAC. Conclusions The early use of DOACs, in a CCG without restrictions to their use, was embraced by primary-care prescribers in this particular CCG.
    • Use of a pathway quality improvement care bundle to reduce mortality after emergency laparotomy

      Huddart, S.; Peden, C.J.; Swart, M.; McCormick, B.; Dickinson, M.; Mohammed, Mohammed A.; Quiney, N. (2015)
      Emergency laparotomies in the U.K., U.S.A. and Denmark are known to have a high risk of death, with accompanying evidence of suboptimal care. The emergency laparotomy pathway quality improvement care (ELPQuiC) bundle is an evidence-based care bundle for patients undergoing emergency laparotomy, consisting of: initial assessment with early warning scores, early antibiotics, interval between decision and operation less than 6 h, goal-directed fluid therapy and postoperative intensive care. The ELPQuiC bundle was implemented in four hospitals, using locally identified strategies to assess the impact on risk-adjusted mortality. Comparison of case mix-adjusted 30-day mortality rates before and after care-bundle implementation was made using risk-adjusted cumulative sum (CUSUM) plots and a logistic regression model. Risk-adjusted CUSUM plots showed an increase in the numbers of lives saved per 100 patients treated in all hospitals, from 6.47 in the baseline interval (299 patients included) to 12.44 after implementation (427 patients included) (P < 0.001). The overall case mix-adjusted risk of death decreased from 15.6 to 9.6 per cent (risk ratio 0.614, 95 per cent c.i. 0.451 to 0.836; P = 0.002). There was an increase in the uptake of the ELPQuiC processes but no significant difference in the patient case-mix profile as determined by the mean Portsmouth Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity risk (0.197 and 0.223 before and after implementation respectively; P = 0.395). Use of the ELPQuiC bundle was associated with a significant reduction in the risk of death following emergency laparotomy.