• 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.
    • Use of batch mixing to investigate the continuous solvent-free mechanical synthesis of OLED materials by twin-screw extrusion (TSE)

      Crawford, Deborah E.; James, S.L.; McNally, T. (2018-01)
      Mechanochemical synthesis has the potential to change the way in which chemistry is conducted, particularly with regard to removing or dramatically reducing the need for solvents. Recently, it has been demonstrated that mechanochemistry can be carried out continuously and on large scale through the use of twin-screw extrusion (TSE). TSE has successfully been applied to the synthesis of cocrystals, metal organic frameworks (MOFs), deep eutectic solvents (DESs), metal complexes, and organic condensation reactions. However, while TSE provides a route for mechanochemical synthesis to be developed into a continuous, high-volume manufacturing process, little is currently understood about how to best optimize the various process parameters involved. Herein, we investigate the use of a batch mixer that has been previously used in polymer processing, to optimize mechanochemical reactions performed by extrusion. In particular, reactions between 8-hydroxyquinoline (Hq) and metal acetate salts of zinc or aluminum to give quinolinate complexes Znq2·AcOH and Alq3·AcOH, which are of interest for organic light-emitting diode (OLED) applications, have been investigated. The manner in which the progress of the reaction correlates with the machine torque, temperature, and specific mechanical energy (SME) imparted by the batch mixer has been elucidated. Significantly, this knowledge enabled optimization of the mechanochemical reactions by TSE through the key parameters of screw speed, feed rate, temperature, and particle size.
    • Use of complementary nucleobase-containing synthetic polymers to prepare complex self-assembled morphologies in water

      Kang, Y.; Pitto-Barry, Anaïs; Rolph, M.S.; Hua, Z.; Hands-Portman, I.; Kirby, N.; O'Reilly, R.K. (2016-04-28)
      Amphiphilic nucleobase-containing block copolymers with poly(oligo(ethylene glycol) methyl ether methacrylate) as the hydrophilic block and nucleobase-containing blocks as the hydrophobic segments were successfully synthesized using RAFT polymerization and then self-assembled via solvent switch in aqueous solutions. Effects of the common solvent on the resultant morphologies of the adenine (A) and thymine (T) homopolymers, and A/T copolymer blocks and blends were investigated. These studies highlighted that depending on the identity of the common solvent, DMF or DMSO, spherical micelles or bicontinuous micelles were obtained. We propose that this is due to the presence of A–T interactions playing a key role in the morphology and stability of the resultant nanoparticles, which resulted in a distinct system compared to individual adenine or thymine polymers. Finally, the effects of annealing on the self-assemblies were explored. It was found that annealing could lead to better-defined spherical micelles and induce a morphology transition from bicontinuous micelles to onion-like vesicles, which was considered to occur due to a structural rearrangement of complementary nucleobase interactions resulting from the annealing process.
    • The use of corsetry to treat Pott’s disease of the spine from 19th Century Wolverhampton, England

      Moore, Joanna; Buckberry, Jo (2016-09)
      Corsets have been used both to create a fashionable silhouette and as an orthopaedic treatment for spinal conditions, but skeletal changes associated with the use of corsetry are rarely reported on in the palaeopathological literature. Here, we report on a 19th-century adult male with Pott’s disease of the vertebral column and related vertebral compression deformities, which probably result from the use of a corset. Wolverhampton HB40 presented destruction of the vertebral bodies of T6 to L4, ankylosis of the apophyseal joints of L1 and L2 and an angular kyphosis of the lumbar region, the result of tuberculosis. The presence of flattened spinous processes and bilateral acute angulation of multiple ribs in the lower thoracic region is indicative of plastic deformation caused by the use of the corset. The presence of both of these changes in an adult male, at a time when the use of cosmetic corsets by men was in decline, suggests that the compression trauma was the result of an orthopaedic corset used to correct the defective posture resulting from tubercular kyphosis, although corset use to obtain a fashionable silhouette cannot be ruled out.
    • The use of isolated peripheral lymphocytes and human whole blood in the comet assay

      Najafzadeh, Mojgan; Anderson, Diana (2016-10-27)
      The comet assay is a sensitive method used to detect DNA damage, measuring DNA breaks and alkali labile lesions in eukaryotic cells. Here, the use of whole blood in the alkaline gel electrophoresis method is described. Two hundred and seventy blood samples from individuals were examined: 120 healthy individuals, 65 suspected or pre-cancerous individuals and 85 cancer patients. Each sample was divided into two identical volumes in different falcon tubes. The blood was prepared and stored by adding the same amount of RPMI medium and 10% DMSO. Using the Student’s t-Test, the data showed a p value = 0.59 for Olive tail moment (OTM) and 0.16 for % tail DNA, and no statistically significant differences between the two methods, with or without treatment. In conclusion, using whole blood instead of isolated lymphocytes saves time, is still very sensitive and requires less than 20 µL of blood from each individual.