• The S-Xanthenyl group: potential for application in the synthesis of thioglycosides.

      Falconer, Robert A. (2002)
      The S-xanthenyl (Xan) group was demonstrated to have potential as a convenient protecting group for 1-thiosugars in the synthesis of thioglycosides. Easily introduced by reaction of a 1-thiosugar with 9-hydroxyxanthene in the presence of catalytic TFA, the S-Xan group is compatible with a wide range of functionalities and protecting groups.
    • S. cerevisiae Srs2 helicase ensures normal recombination intermediate metabolism during meiosis and prevents accumulation of Rad51 aggregates

      Hunt, L.J.; Ahmed, E.A.; Kaur, H.; Ahuja, J.S.; Hulme, L.; Chou, T.C.; Lichten, M.; Goldman, Alastair S.H. (2019-09)
      We investigated the meiotic role of Srs2, a multi-functional DNA helicase/translocase that destabilises Rad51-DNA filaments and is thought to regulate strand invasion and prevent hyper-recombination during the mitotic cell cycle. We find that Srs2 activity is required for normal meiotic progression and spore viability. A significant fraction of srs2 mutant cells progress through both meiotic divisions without separating the bulk of their chromatin, although in such cells sister centromeres often separate. Undivided nuclei contain aggregates of Rad51 colocalised with the ssDNA-binding protein RPA, suggesting the presence of persistent single-strand DNA. Rad51 aggregate formation requires Spo11-induced DSBs, Rad51 strand-invasion activity and progression past the pachytene stage of meiosis, but not the DSB end-resection or the bias towards interhomologue strand invasion characteristic of normal meiosis. srs2 mutants also display altered meiotic recombination intermediate metabolism, revealed by defects in the formation of stable joint molecules. We suggest that Srs2, by limiting Rad51 accumulation on DNA, prevents the formation of aberrant recombination intermediates that otherwise would persist and interfere with normal chromosome segregation and nuclear division.
    • The safety and continuity of medicines at transitions of care for people with heart failure

      Fylan, Beth; Armitage, Gerry R.; Breen, Liz; Gardner, Peter H.; Ismail, Hanif; Marques, Iuri; Blenkinsopp, Alison (2017-03-23)
      Avoidable harm associated with medicines is widespread – particularly at care transitions – and unintended discrepancies in patients’ medicines after discharge from hospital affect more than half of all patients. Patients with heart failure are frequent service users (including readmission to hospital), and susceptible to deficiencies in medicines management. Heart failure is responsible for approximately 5% of medical admissions and the readmission rate within 3 months of discharge may be as high as 50%.[1] The Improving Safety and Continuity of Medicines management at Transitions of care (ISCOMAT) study is an NIHR-funded programme of research in patients with heart failure. The first work package, described here, aimed to map and evaluate current medicines management pathways across care transitions, describing the core characteristics of best practice and effective systems at each stage. Mixed-methods research collecting data centred on patients’ journey out of hospital and back home exploring current practice relating on heart failure. NHS REC approval was obtained (16/NS/0018). Following a process of informed consent, data were collected from patients (n=16) in four health economies in England using semi-structured interviews conducted shortly after their discharge from hospital and again after two and six weeks and included video recording. Non-participant observation was conducted on cardiology wards in the four areas to understand predominant systems employed by the hospitals to deliver information to patients and to primary care. Interviews with staff in hospitals and primary care explored policy, practice and systems across the transition. Data were analysed using integrative ‘parallel mixed’ analysis. Several themes emerged that described the resilience of the system that manages patients’ medicines across the whole pathway. Spatial dimensions – including local working conditions – impacted on staff who managed transfers. Process efficiencies and effectiveness, including the degree of staff training and policy awareness, both enhanced and hindered communication with patients and health care professionals (HCPs) in primary care. The system did not allow staff to assess the impact of the management of medicines at discharge across the transition into primary care. Patients themselves were found to have different levels of knowledge and confidence in their medicines once back at home and, where their pathway included this, to value the care co-ordination functions of heart failure nurses. Primary care staff operated varying systems for managing discharge communication and implementing recommendations and some reported positive outcomes from integration of practice pharmacists into the system. To our knowledge this is the first UK study of medicines management along the patient’s journey from hospital into primary care for patients with heart failure. A whole pathway analysis has enabled a detailed understanding of resilience in each part of the healthcare system. These findings will be used in the co-design of an intervention to improve medicines management in the next phase of the research.
    • Safety and quality of nurse independent prescribing: a national study of experiences of education, continuing professional development clinical governance

      Smith, A.; Latter, S.; Blenkinsopp, Alison (2014-10-13)
      Aim. To determine the adequacy of initial nurse independent prescribingeducation and identify continuing professional development and clinicalgovernance strategies in place for non-medical prescribing.Background. In 2006, new legislation in England enabled nurses with anindependent prescribing qualification to prescribe, within their competence. In 2006,non-medical prescribing policies released by the Department of Health outlinedthe recommendations for education, continuing professional development andgovernance of non-medical prescribing; however, there was no evidence on a nationalscale about the exte nt of implementation and effectiveness of these strategies.Design. National surveys of: (i) nurse independent prescribers; and (ii) non-medical prescribing leaders in England.Methods. Questionnaire surveys (August 2008–February 2009) coveringeducational preparation, prescribing practice (nurse independent prescribers) andstructures/processes for support and governance (non-medical prescribing leaders).Results. Response rates were 65% (976 prescribers) and 52% (87 leaders). Mostnurses felt their prescribing course met their learning needs and stated courseoutcomes and that they had adequate development and support for prescribing tomaintain patient safety. Some types of community nurse prescribers had less accessto support and development. The prescribing leaders reported lacking systems toensure continuity of non-medical prescribing and monitoring patient experience.Conclusion. Educational programmes of preparation for nurse prescribing werereported to be operating satisfactorily and providing fit-for-purpose preparationfor the expansion to the scope of nurse independent prescribing. Most clinicalgovernance and risk management strategies for prescribing were in place inprimary and secondary care.
    • Safety on stairs: Influence of a tread edge highlighter and its position

      Foster, Richard J.; Hotchkiss, John; Buckley, John G.; Elliott, David B. (2014-07)
      Background: Falls sustained when descending stairs are the leading cause of accidental death in older adults. Highly visible edge highlighters/friction strips (often set back from the tread edge) are sometimes used to improve stair safety, but there is no evidence for the usefulness of either. Objective: To determine whether an edge highlighter and its location relative to the tread edge affect foot placement/clearance and accidental foot contacts when descending stairs. Method: Sixteen older adults (mean ± 1 SD age; 71 ± 7 years) with normal vision (experiment 1) and eight young adults (mean ± 1 SD age; 24 ± 4 years) with visual impairment due to simulated age-related cataract (experiment 2) completed step descent trials during which a high contrast edge highlighter was either not present, placed flush with the tread edge, or set back from the edge by 10 mm or 30 mm. Foot placement/ clearance and the number of accidental foot contacts were compared across conditions. Results: In experiment 1, a highlighter set back by 30 mm led to a reduction in final foot placement (p b 0.001) and foot clearance (p b 0.001) compared to a highlighter placed flush with the tread edge, and the percentage of foot clearances that were less than 5 mm increased from 2% (abutting) to 17% (away30). In experiment 2, a highlighter placed flushwith the tread edge led to a decrease in within-subject variability in final foot placement (p = 0.004) and horizontal foot clearance (p = 0.022), a decrease in descent duration (p = 0.009), and a decrease in the number of low clearances (b5 mm, from 8% to 0%) and the number of accidental foot contacts (15% to 3%) when compared to a tread edge with no highlighter present. Conclusions: Changes to foot clearance parameters as a result of highlighter presence and position suggest that stairswith high-contrast edge highlighters positioned flushwith the tread edgewill improve safety on stairs, particularly for those with age-related visual impairment.
    • The scaffold protein KSR1, a novel therapeutic target for the treatment of Merlin-deficient tumors

      Zhou, L.; Lyons-Rimmer, J.; Ammoun, S.; Muller, Jurgen; Lasonder, E.; Sharma, V.; Ercolano, E.; Hilton, D.; Taiwo, I.; Barczyk, M.; et al. (2016-06-30)
      Merlin has broad tumor-suppressor functions as its mutations have been identified in multiple benign tumors and malignant cancers. In all schwannomas, the majority of meningiomas and 1/3 of ependymomas Merlin loss is causative. In neurofibromatosis type 2, a dominantly inherited tumor disease because of the loss of Merlin, patients suffer from multiple nervous system tumors and die on average around age 40. Chemotherapy is not effective and tumor localization and multiplicity make surgery and radiosurgery challenging and morbidity is often considerable. Thus, a new therapeutic approach is needed for these tumors. Using a primary human in vitro model for Merlin-deficient tumors, we report that the Ras/Raf/mitogen-activated protein, extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) scaffold, kinase suppressor of Ras 1 (KSR1), has a vital role in promoting schwannomas development. We show that KSR1 overexpression is involved in many pathological phenotypes caused by Merlin loss, namely multipolar morphology, enhanced cell-matrix adhesion, focal adhesion and, most importantly, increased proliferation and survival. Our data demonstrate that KSR1 has a wider role than MEK1/2 in the development of schwannomas because adhesion is more dependent on KSR1 than MEK1/2. Immunoprecipitation analysis reveals that KSR1 is a novel binding partner of Merlin, which suppresses KSR1's function by inhibiting the binding between KSR1 and c-Raf. Our proteomic analysis also demonstrates that KSR1 interacts with several Merlin downstream effectors, including E3 ubiquitin ligase CRL4(DCAF1). Further functional studies suggests that KSR1 and DCAF1 may co-operate to regulate schwannomas formation. Taken together, these findings suggest that KSR1 serves as a potential therapeutic target for Merlin-deficient tumors.
    • SCF - Engineered powders for delivery of budesonide from passive DPI devices.

      York, Peter; Lobo, J.M.; Palakodaty, S.; Schiavone, H.; Clark, A.; Tzannis, S.T. (2005)
      The objective of this study was to develop SEDS-engineered budesonide particles suitable for dry powder inhalation delivery and to evaluate their aerosol performance across a range of passive dry powder inhalers (DPI). SEDS budesonide powders were manufactured in Nektar's SCF manufacturing plant and compared to the micronized drug and commercial powder (Pulmicort Turbuhaler, AstraZeneca). Aerosol performance was evaluated by determining emitted dose (ED) by a variation of the USP method and fine particle fraction (FPF) using Andersen cascade impaction. The SCF powder dispersed best in the Turbospin and Eclipse devices, exhibiting high EDs (70%-80%) and relatively low variability (RSD 8%-13%). Regardless of the device, the SEDS material outperformed both the micronized drug and the commercial powder, while exhibiting good batch-to-batch reproducibility (RSD <5%). All powders exhibited flow rate-dependent ED, albeit for the SEDS material it was minimized at reduced fill weights. This was attributed to inadequate and variable powder clearance from the capsules at low inspiratory flow rates, which was more pronounced in the Eclipse and Cyclohaler. The results demonstrate that SEDS is an attractive particle-engineering process that may enhance pulmonary performance of budesonide and possibly facilitate development of other small molecule pulmonary products in passive DPI.
    • Schizophrenia: synthetic strategies and recent advances in drug design

      Azmanova, Maria; Pitto-Barry, Anaïs; Barry, Nicolas P.E. (2018)
      Schizophrenia is a complex and unpredictable mental disorder which affects several domains of cognition and behaviour. It is a heterogeneous illness characterised by positive, negative, and cognitive symptoms, often accompanied by signs of depression. In this tutorial review, we discuss recent progress in understanding the target sites and mechanisms of action of second-generation antipsychotic drugs. Progress in identifying and defining target sites has been accelerated recently by advances in neuroscience, and newly developed agents that regulate signalling by the main excitatory neurotransmitters in the brain are surveyed. Examples of novel molecules for the treatment of schizophrenia in preclinical and clinical development and their industrial sponsors are highlighted.
    • The Schlumberger array - potential and pitfalls in archaeological prospection

      Gaffney, Christopher F.; Aspinall, A. (2001)
      The orientation-sensitive performance of the Schlumberger array, when used to survey narrow, linear features, has long been recognized in geophysical prospecting for geology. However, in spite of frequent use of the array for archaeological survey, particularly in eastern Europe and the Far East, this directional effect is not apparent in the survey of walls and ditches. In order to examine the array's performance some experiments were carried out in a shallow electrolytic tank using insulating and conducting cylinders. Broadside and longitudinal traverses with systematic expansion of the current electrode spacing facilitated the production of pseudosections. The results confirmed the high selectivity of the Schlumberger response to the orientation of the feature. Broadside traverse of the conductor and longitudinal traverse of the insulator produced very large changes: much smaller signals were recorded for the alternative orientations. A subsequent experiment, however, on a simulated ditch in bedrock revealed no signal. The directional effect for a linear insulator was confirmed in field studies of a simple stone-walled structure. Implications for survey of low-contrast linear archaeological features are discussed.
    • Scientific Analysis of Steatite: Recent results.

      Clelland, Sarah-Jane; Batt, Catherine M.; Stern, Ben; Jones, R.E. (2009)
    • Scleroderma fibroblasts suppress angiogenesis via TGF-β/caveolin-1 dependent secretion of pigment epithelium-derived factor

      Liakouli, V.; Elies, Jacobo; El-Sherbiny, Y.M.; Scarcia, M.; Grant, G.; Abignano, G.; Derrett-Smith, E.C.; Esteves, F.; Cipriani, P.; Emery, P.; et al. (2018-03)
      Objectives Systemic sclerosis (SSc) is characterised by tissue fibrosis and vasculopathy with defective angiogenesis. Transforming growth factor beta (TGF-β) plays a major role in tissue fibrosis, including downregulation of caveolin-1 (Cav-1); however, its role in defective angiogenesis is less clear. Pigment epithelium-derived factor (PEDF), a major antiangiogenic factor, is abundantly secreted by SSc fibroblasts. Here, we investigated the effect of TGF-β and Cav-1 on PEDF expression and the role of PEDF in the ability of SSc fibroblasts to modulate angiogenesis. Methods P EDF and Cav-1 expression in fibroblasts and endothelial cells were evaluated by means of immunohistochemistry on human and mouse skin biopsies. PEDF and Cav-1 were silenced in cultured SSc and control fibroblasts using lentiviral short-hairpin RNAs. Organotypic fibroblast–endothelial cell cocultures and matrigel assays were employed to assess angiogenesis. Results P EDF is highly expressed in myofibroblasts and reticular fibroblasts with low Cav-1 expression in SSc skin biopsies, and it is induced by TGF-β in vitro. SSc fibroblasts suppress angiogenesis in an organotypic model. This model is reproduced by silencing Cav-1 in normal dermal fibroblasts. Conversely, silencing PEDF in SSc fibroblasts rescues their antiangiogenic phenotype. Consistently, transgenic mice with TGF-β receptor hyperactivation show lower Cav-1 and higher PEDF expression levels in skin biopsies accompanied by reduced blood vessel density. Conclusions O ur data reveal a new pathway by which TGF-β suppresses angiogenesis in SSc, through decreased fibroblast Cav-1 expression and subsequent PEDF secretion. This pathway may present a promising target for new therapeutic interventions in SSc.
    • Screening Indian plant species for antiplasmodial properties – ethnopharmacological compared to random selection.

      Kantamreddi, Venkata Siva Satya Narayana; Wright, Colin W. (2012-12)
      In the search for biologically active plant species, many studies have shown that an ethnopharmacological approach is more effective than a random collection. In order to determine whether this is true in the case of plant species used for the treatment of malaria in Orissa, India, the antiplasmodial activities of extracts prepared from 25 traditionally used species were compared with those of 25 species collected randomly. As expected, plant species used traditionally for the treatment of malaria were more likely to exhibit antiplasmodial activity (21 species (84%) active against Plasmodium falciparum strain 3D7) than plant species collected randomly (9 species (32%)). However, of the nine active randomly collected species, eight had not previously been reported to possess antiplasmodial activity while one inactive species had been reported to be active in another study. Of the 21 active species of traditional antimalarial treatments, only six had been reported previously. This study suggests that while the selection of traditional medicinal plants is more predictive of antiplasmodial study, random collections may still be of value for the identification of new antiplasmodial species.
    • Screening of Tanzanian medicinal plants against Plasmodium falciparum and human immunodeficiency virus.

      Maregesi, S.; Van Miert, S.; Pannecouque, C.; Feiz-Haddad, M.H.; Hermans, N.; Wright, Colin W.; Vlietinck, A. J.; Aspers, S.; Pieters, L. (Theime, 2010)
      Medicinal plants used to treat infectious diseases in Bunda district, Tanzania, were screened for activity against Plasmodium falciparum and human Immunodeficiency Virus Type 1 (HIV-1, IIIB strain) and Type 2 (HIV-2, ROD strain). Antiplasmodial activity was observed for the 80% MeOH extract of Ormocarpum kirkii (root; MIC = =31.25 ¿g/mL). Combretum adenogonium (leaves), Euphorbia tirucalli (root), Harrisonia abyssinica (root), Rhyncosia sublobata (root), Sesbania sesban (root), Tithonia diversifolia (leaves), and Vernonia cinerascens (leaves; MIC value of 62.5 ¿g/mL). With regard to HIV, 80% MeOH extracts of Barleria eranthemooides (root), Cambretum adenogonium (leaves and stem bark), Elaeodedron schlechteranum (stem bark and root bark), Lannea schweinfurthii (stem bark), Terminalia mollis (stem bark and root bark), Acacia tortilis (stem bark), Ficus cycamorus (stem bark) and Indigofera colutea (shoot), as well as H2O extracts from Barleria eranthemoides (root), Combretum adenogonium (leaves and stem bark)and Terminalia mollis (stem bark and root bark) exhibited IC50 values below 10 ¿g/mL against HIV-1 (IIIB strain). The highest anti-HIV-1 activity value was obtained for the B. eranthemoides 80% MeOH root extract (IC50 value 2.1 ¿g/mL). Only a few extracts were active against HIV-2, such as the 80% MeOH extract from Lannea schweinfurthii (stem bark) and Elaeodedron schlechteranum (root bark), showing IC50 values < 10 ¿g/mL.
    • Screening of textiles for contraband drugs using portable Raman spectroscopy and chemometrics

      Ali, Esam M.A.; Edwards, Howell G.M. (2014)
      The impregnation of items of clothing with drugs of abuse that are then smuggled through airports and ports of entry is a growing problem for law enforcement. This work describes the application of portable Raman spectroscopic techniques for the analysis of a range of natural and artificial fibre items of clothing impregnated with drugs of abuse. Textile pieces were soaked with the solutions of the drugs then left overnight to dry prior to spectroscopic examination. The feasibility of detection of the characteristic Raman spectral bands in the presence of background matrix signals is demonstrated, even for dyed clothing. Definitive evidence for contamination of the items of clothing concerned can be acquired within 20-25 s, without any form of sample pre-treatment or extraction being necessary. The feasibility of automatic spectral recognition of such illicit materials by Raman spectroscopy has been investigated by searching a database stored on the spectrometer computer and the use of principal component analysis. Copyright (c) 2014 John Wiley & Sons, Ltd.
    • Scytonin, a novel cyanobacterial photoprotective pigment: calculations of Raman spectroscopic biosignatures

      Varnali, T.; Edwards, Howell G.M. (2014-03)
      The Raman spectrum of scytonin, a novel derivative of the parent scytonemin, is predicted from DFT calculations of the most stable, lowest energy, conformational structure. The diagnostic importance of this study relates to the spectral ability to discriminate between scytonemin and its derivatives alone or in admixture with geological matrices from identified characteristic Raman spectral signatures. The successful interpretation of biosignatures from a wide range of cyanobacterial extremophilic colonization in terrestrial and extraterrestrial scenarios is a fundamental requirement of the evaluation of robotic spectroscopic instrumentation in search for life missions. Scytonemin is produced exclusively by cyanobacterial colonies in environmentally stressed habitats and is widely recognized as a key target biomarker molecule in this enterprise. Here, the detailed theoretical analysis of the structure of scytonin enables a protocol to be established for the recognition of characteristic bands in its Raman spectrum and to accomplish the successful differentiation between scytonin and scytonemin as well as other scytonemin derivatives such as the dimethoxy and tetramethoxy compounds that have been isolated from cyanobacterial colonies but which have not yet been characterized spectroscopically. The results of this study will facilitate an extension of the database capability for miniaturized Raman spectrometers which will be carried on board search for life robotic missions to Mars, Europa, and Titan.
    • Searching for new treatments of malaria

      Wright, Colin W. (2015-10)
      The aim of this chapter is to illustrate some current developments in natural product-derived antimalarial drugs. Traditional medicines have provided two of our most important antimalarial drugs (quinine and artemisinin) and have the potential to provide many novel antimalarial lead compounds of which several examples will be discussed. In addition, well- known natural antimalarials such as artemisinin continue to be an important focus of research and there is also increasing interest in investigating natural product sources that have not been traditionally used as antimalarials such as marine species of plants and animals. Assays based on specific malaria parasite targets such as thioredoxin reductase and heat shock protein have been employed to screen extracts and/or compounds and these have resulted in the identification of a number of potentially interesting antiplasmodial agents. However, since many victims of malaria are unable to afford antimalarial drugs, another approach adopted by some charities/NGO’s is to encourage people to grow their own medicinal plants such as Artemisia annua; some recent studies on this theme will be discussed.
    • A seasonal switch in histone deacetylase gene expression in the hypothalamus and their capacity to modulate nuclear signaling pathways

      Stoney, P.N.; Rodrigues, D.; Helfer, Gisela; Khatib, T.; Ashton, A.; Hay, E.A.; Starr, R.; Kociszewska, D.; Morgan, P.J.; McCaffery, P.J. (2016)
      Seasonal animals undergo changes in physiology and behavior between summer and winter conditions. These changes are in part driven by a switch in a series of hypothalamic genes under transcriptional control by hormones and, of recent interest, inflammatory factors. Crucial to the control of transcription are histone deacetylases (HDACs), generally acting to repress transcription by local histone modification. Seasonal changes in hypothalamic HDAC transcripts were investigated in photoperiod-sensitive F344 rats by altering the day-length (photoperiod). HDAC4, 6 and 9 were found to change in expression. The potential influence of HDACs on two hypothalamic signaling pathways that regulate transcription, inflammatory and nuclear receptor signaling, was investigated. For inflammatory signaling the focus was on NF-κB because of the novel finding made that its expression is seasonally regulated in the rat hypothalamus. For nuclear receptor signaling it was discovered that expression of retinoic acid receptor beta was regulated seasonally. HDAC modulation of NF-κB-induced pathways was examined in a hypothalamic neuronal cell line and primary hypothalamic tanycytes. HDAC4/5/6 inhibition altered the control of gene expression (Fos, Prkca, Prkcd and Ptp1b) by inducers of NF-κB that activate inflammation. These inhibitors also modified the action of nuclear receptor ligands thyroid hormone and retinoic acid. Thus seasonal changes in HDAC4 and 6 have the potential to epigenetically modify multiple gene regulatory pathways in the hypothalamus that could act to limit inflammatory pathways in the hypothalamus during long-day summer-like conditions.
    • Secretory phospholipase A2 as a tumor specific trigger for targeted delivery of a novel class of liposomal prodrug anticancer etherlipids

      Gill, Jason H.; Bibby, Michael C.; Jensen, S.S.; Shnyder, Steven D. (2004)
      The use of many common clinically relevant chemotherapeutics is often limited due to insufficient delivery to the tumor and dose-limiting systemic toxicities. Therefore, therapeutics that specifically target tumor cells and are nontoxic to normal cells are required. Here, we report the development of a novel class of liposomes composed of lipid prodrugs, which use the increased secretory phospholipase A2 type IIA (sPLA2) activity of the tumor microenvironment as a trigger for the release of anticancer etherlipids (AEL). Treatment of sPLA2-secreting tumor cells in vitro with liposomes consisting of proAELs resulted in growth inhibition comparable with addition of the AELs alone. Using a specific sPLA2 inhibitor, we showed the low cytotoxicity of the nonhydrolyzed proAEL liposomes and have proven the sPLA2 dependency of the activation of proAELs to cytotoxic AELs. In addition, we showed that our proAEL liposomes circumvent the inherent hemolytic toxicities associated with the use of etherlipids, thereby allowing i.v. administration of such therapeutics as nontoxic prodrug liposomes. Furthermore, using a sPLA2-secreting human colon cancer xenograft model, we showed that the proAEL liposomes are capable of inducing a tumor growth delay in vivo. Taken together, these data support the validity of this novel tumor-selective liposomal prodrug delivery strategy. This new approach also provides a promising system for tumor-selective delivery and release of conventional chemotherapeutics encapsulated in the sPLA2-degradable prodrug liposomes.