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  • pH Dependence of Acrylate-Derivative Polyelectrolyte Properties

    Swift, Thomas (2019-03-14)
    There are many polymers formed of acrylate monomers in existence. Here we interrogate four commonly-used examples and study how their solution properties are pH dependent, or how their state of ionisation can affect their solution properties. Poly(acrylic acid) and poly(methacrylic acid) are both polyelectrolytes, with ionisable functional groups that make them stimuli responsive, changing their hydrodynamic volume. Poly(acrylamide) is a mass-produced material used in a variety of industrial applications, often with an anionic and cationic co-monomer, which dictates both its efficacy and impact on the environment. Poly(N-isopropyl acrylamide) is a thermally responsive material with applications in smart bioengineering. In solution, these materials can interact with each other due to competing hydrogen bonding interactions. However, this interpolymer complexation is dependent on both the ionisation, and the conformational state, of the polymers involved. This review focuses on the results from fluorescence tagging and turbidimetric techniques.
  • Targeting the mesolithic: Interdisciplinary approaches to archaeological prospection inthe Brown Bank area, southern North Sea

    Missiaen, T.; Fitch, Simon; Muru, Merle; Harding, Rachel; Fraser, Andy; De Clercq, M.; Garcia Moreno, David; Versteeg, W.; Gaffney, Vincent L. (2020)
    This paper describes some results of the research undertaken over the Brown Bank area during recent (2018/2019) geoarchaeological surveys in the North Sea which included seismic imaging, shallow (vibro)coring and dredging. It examines the benefits of simultaneous high-resolution (0.5 – 1m) and ultra-high-resolution (10 – 20cm) seismic survey techniques and a staged approach to resolving the submerged Holocene landscape in the highest possible detail for the purpose of targeted prospecting for archaeological material from the Mesolithic landscape of Doggerland. The materials recovered from such surveys offer significantly greater information due to an enhanced understanding of the context in which they were recovered. The importance of this information cannot be understated archaeologically, as few locations on land provide the opportunity to recover archaeological finds in situ within preserved landscapes. Moreover, it allows offshore areas of potential human activity to be prospected with some certainty of success.
  • PIA: More Accurate Taxonomic Assignment of Metagenomic Data Demonstrated on sedaDNA From the North Sea

    Gaffney, Vincent L.; Cribdon, B.; Ware, R.; Smith, O.; Allaby, R. (2020-04-03)
    Assigning metagenomic reads to taxa presents significant challenges. Existing approaches address some issues, but are mostly limited to metabarcoding or optimized for microbial data. We present PIA (Phylogenetic Intersection Analysis): a taxonomic binner that works from standard BLAST output while mitigating key effects of incomplete databases. Benchmarking against MEGAN using sedaDNA suggests that, while PIA is less sensitive, it can be more accurate. We use known sequences to estimate the accuracy of PIA at up to 96% when the real organism is not represented in the database. For ancient DNA, where taxa of interest are frequently over-represented domesticates or absent, poorly-known organisms, more accurate assignment is critical, even at the expense of sensitivity. PIA offers an approach to objectively filter out false positive hits without the need to manually remove taxa and so make presuppositions about past environments and their palaeoecologies.
  • Ewastools: Infinium Human Methylation BeadChip pipeline for population epigenetics integrated into Galaxy

    Murat, Katarzyna; Grüning, B.; Poterlowicz, P.W.; Westgate, Gillian E.; Tobin, Desmond J.; Poterlowicz, Krzysztof (Oxford Academic, 2020-05)
    Infinium Human Methylation BeadChip is an array platform for complex evaluation of DNA methylation at an individual CpG locus in the human genome based on Illumina’s bead technology and is one of the most common techniques used in epigenome-wide association studies. Finding associations between epigenetic variation and phenotype is a significant challenge in biomedical research. The newest version, HumanMethylationEPIC, quantifies the DNA methylation level of 850,000 CpG sites, while the previous versions, HumanMethylation450 and HumanMethylation27, measured >450,000 and 27,000 loci, respectively. Although a number of bioinformatics tools have been developed to analyse this assay, they require some programming skills and experience in order to be usable. Results We have developed a pipeline for the Galaxy platform for those without experience aimed at DNA methylation analysis using the Infinium Human Methylation BeadChip. Our tool is integrated into Galaxy (http://galaxyproject.org), a web-based platform. This allows users to analyse data from the Infinium Human Methylation BeadChip in the easiest possible way. Conclusions The pipeline provides a group of integrated analytical methods wrapped into an easy-to-use interface. Our tool is available from the Galaxy ToolShed, GitHub repository, and also as a Docker image. The aim of this project is to make Infinium Human Methylation BeadChip analysis more flexible and accessible to everyone.
  • Pleiotropic Effects of Proopiomelanocortin and VGF Nerve Growth Factor Inducible Neuropeptides for the Long-Term Regulation of Energy Balance

    Helfer, Gisela; Stevenson, T.J. (2020)
    Seasonal rhythms in energy balance are well documented across temperate and equatorial zones animals. The long-term regulated changes in seasonal physiology consists of a rheostatic system that is essential to successful time annual cycles in reproduction, hibernation, torpor, and migration. Most animals use the annual change in photoperiod as a reliable and robust environmental cue to entrain endogenous (i.e. circannual) rhythms. Research over the past few decades has predominantly examined the role of first order neuroendocrine peptides for the rheostatic changes in energy balance. These anorexigenic and orexigenic neuropeptides in the arcuate nucleus include neuropeptide y (Npy), agouti-related peptide (Agrp), cocaine and amphetamine related transcript (Cart) and pro-opiomelanocortin (Pomc). Recent studies also indicate that VGF nerve growth factor inducible (Vgf) in the arcuate nucleus is involved in the seasonal regulation of energy balance. In situ hybridization, qPCR and RNA-sequencing studies have identified that Pomc expression across fish, avian and mammalian species, is a neuroendocrine marker that reflects seasonal energetic states. Here we highlight that long-term changes in arcuate Pomc and Vgf expression is conserved across species and may provide rheostatic regulation of seasonal energy balance.
  • One-Pot Stepwise Approach to β-Enaminoketoesters through “Masked” 1,3-Aza-Dipoles

    Yan, Z.; Wu, Na (Anna); Liang, D.; Wang, H.; Pan, Y. (2014-08-01)
    t-BuOK-mediated rearrangement of 1,3-ketoesters with 2-(azidomethyl) aromatics in a two-step, one-pot telescoped sequence affords β-enaminoketoesters in moderate to good yields. A novel pathway is proposed in which the umpolung of the azide is achieved from electrophilicity to nucleophilicity via deprotonation and undergoes nucleophilic attack onto the 1,3-ketoester.
  • Ex vivo/in vitro protective effect of myricetin bulk and nano-forms on PhIP-induced DNA damage in lymphocytes from healthy individuals and pre-cancerous MGUS patients

    Akhtar, Shabana; Najafzadeh, Mojgan; Isreb, Mohammad; Newton, L.; Gopalan, Rajendran C.; Anderson, Diana (2020)
    2-Amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) is a central dietary mutagen, produced when proteinaceous food is heated at very high temperatures potentially causing DNA strand breaks. This study investigates the protective potential of a well-researched flavonoid, myricetin in its bulk and nano-forms against oxidative stress induced ex vivo/in vitro by PhIP in lymphocytes from pre-cancerous monoclonal gammopathy of undetermined significance (MGUS) patients and those from healthy individuals. The results from the Comet assay revealed that in the presence of myricetin bulk (10 µM) and myricetin nano (20 µM), the DNA damage caused by a high dose of PhIP (100 µM) was significantly (P < 0.001) reduced in both groups. However, nano has shown better protection in lymphocytes from pre-cancerous patients. Consistent results were obtained from the micronucleus assay where micronuclei frequency in binucleated cells significantly decreased upon supplementing PhIP with myricetin bulk (P < 0.01) and myricetin nano (P < 0.001), compared to the PhIP treatment alone. To briefly determine the cellular pathways involved in the protective role of myricetin against PhIP, we studied gene expression of P53 and ATR kinase (ATM- and Rad3-related), using the real-time PCR technique.
  • Osteoinduction of 3D printed particulate and short-fibre reinforced composites produced using PLLA and apatite-wollastonite

    Melo, P.; Ferreira, A-M.; Waldron, K.; Swift, Thomas; Gentile, P.; Magallanes, M.; Marshall, M.; Dalgarno, K. (2019-11)
    Composites have clinical application for their ability to mimic the hierarchical structure of human tissues. In tissue engineering applications the use of degradable biopolymer matrices reinforced by bioactive ceramics is seen as a viable process to increase osteoconductivity and accelerate tissue regeneration, and technologies such as additive manufacturing provide the design freedom needed to create patient-specific implants with complex shapes and controlled porous structures. In this study a medical grade poly(l-lactide) (PLLA) was used as matrix while apatite-wollastonite (AW) was used as reinforcement (5 wt% loading). Premade rods of composite were pelletized and processed to create a filament with an average diameter of 1.6 mm, using a twin-screw extruder. The resultant filament was 3D printed into three types of porous woodpile samples: PLLA, PLLA reinforced with AW particles, and PLLA with short AW fibres. None of the samples degraded in phosphate buffered solution over a period of 8 weeks, and an average effective modulus of 0.8 GPa, 1 GPa and 1.5 GPa was obtained for the polymer, particle and fibre composites, respectively. Composite samples immersed in simulated body fluid exhibited bioactivity, producing a surface apatite layer. Furthermore, cell viability and differentiation were demonstrated for human mesenchymal stromal cells for all sample types, with mineralisation detected solely for biocomposites. It is concluded that both composites have potential for use in critical size bone defects, with the AW fibre composite showing greater levels of ion release, stimulating more rapid cell proliferation and greater levels of mineralisation.
  • Developments in silicone technology for use in stoma care

    Swift, Thomas; Westgate, Gillian E.; Van Onselen, J.; Lee, S. (2020-03)
    Soft silicone's flexibility, adhesive capacity and non-toxic, non-odourous and hypoallergenic nature have made it an established material for adhesive and protective therapeutic devices. In wound care, silicone is a component of contact layer dressings for superficial wounds and silicone gel sheeting for reducing the risk of scarring, as well as of barriers for incontinence-associated dermatitis. Regarding stoma accessories, silicone is established in barrier films to prevent contact dermatitis, adhesive removers to prevent skin stripping and filler gels to prevent appliance leaks. Until recently, silicone has not been used in stoma appliances flanges, as its hydrophobic nature has not allowed for moisture management to permit trans-epidermal water loss and prevent maceration. Traditional hydrocolloid appliances manage moisture by absorbing water, but this can lead to saturation and moisture-associated skin damage (MASD), as well as increased adhesion and resultant skin tears on removal, known as medical adhesive-related skin injury (MARSI). However, novel silicone compounds have been developed with a distinct evaporation-based mechanism of moisture management. This uses colloidal separation to allow the passage of water vapour at a rate equivalent to normal trans-epidermal water loss. It has been shown to minimise MASD, increase wear time and permit atraumatic removal without the use of adhesive solvents. Trio Healthcare has introduced this technology with a range of silicone-based flange extenders and is working with the University of Bradford Centre for Skin Sciences on prototype silicone-based stoma appliance flanges designed to significantly reduce the incidence of peristomal skin complications, such as MARSI and MASD. It is hoped that this will also increase appliance wear time, reduce costs and improve patient quality of life.
  • Structure and function of the bacterial heterodimeric ABC transporter CydDC: stimulation of ATPase activity by thiol and heme compounds.

    Yamashita, M.; Shepherd, M.; Booth, W.I.; Xie, H.; Postis, V.; Nyathi, Yvonne; Tzokov, S.B.; Poole, R.K.; Baldwin, S.A.; Bullough, P.A. (2014-08)
    In Escherichia coli, the biogenesis of both cytochrome bd-type quinol oxidases and periplasmic cytochromes requires the ATP-binding cassette-type cysteine/GSH transporter, CydDC. Recombinant CydDC was purified as a heterodimer and found to be an active ATPase both in soluble form with detergent and when reconstituted into a lipid environment. Two-dimensional crystals of CydDC were analyzed by electron cryomicroscopy, and the protein was shown to be made up of two non-identical domains corresponding to the putative CydD and CydC subunits, with dimensions characteristic of other ATP-binding cassette transporters. CydDC binds heme b. Detergent-solubilized CydDC appears to adopt at least two structural states, each associated with a characteristic level of bound heme. The purified protein in detergent showed a weak basal ATPase activity (approximately 100 nmol Pi/min/mg) that was stimulated ∼3-fold by various thiol compounds, suggesting that CydDC could act as a thiol transporter. The presence of heme (either intrinsic or added in the form of hemin) led to a further enhancement of thiol-stimulated ATPase activity, although a large excess of heme inhibited activity. Similar responses of the ATPase activity were observed with CydDC reconstituted into E. coli lipids. These results suggest that heme may have a regulatory role in CydDC-mediated transmembrane thiol transport.
  • Analysis of the interplay of protein biogenesis factors at the ribosome exit site reveals new role for NAC

    Nyathi, Yvonne; Pool, M.R. (2015-07)
    The ribosome exit site is a focal point for the interaction of protein-biogenesis factors that guide the fate of nascent polypeptides. These factors include chaperones such as NAC, N-terminal-modifying enzymes like Methionine aminopeptidase (MetAP), and the signal recognition particle (SRP), which targets secretory and membrane proteins to the ER. These factors potentially compete with one another in the short time-window when the nascent chain first emerges at the exit site, suggesting a need for regulation. Here, we show that MetAP contacts the ribosome at the universal adaptor site where it is adjacent to the α subunit of NAC. SRP is also known to contact the ribosome at this site. In the absence of NAC, MetAP and SRP antagonize each other, indicating a novel role for NAC in regulating the access of MetAP and SRP to the ribosome. NAC also functions in SRP-dependent targeting and helps to protect substrates from aggregation before translocation.
  • Binding of SGTA to Rpn13 selectively modulates protein quality control

    Leznicki, P.; Korac-Prlic, J.; Kliza, K.; Husnjak, K.; Nyathi, Yvonne; Dikic, I.; High, S. (2015-09)
    Rpn13 is an intrinsic ubiquitin receptor of the 26S proteasome regulatory subunit that facilitates substrate capture prior to degradation. Here we show that the C-terminal region of Rpn13 binds to the tetratricopeptide repeat (TPR) domain of SGTA, a cytosolic factor implicated in the quality control of mislocalised membrane proteins (MLPs). The overexpression of SGTA results in a substantial increase in steady-state MLP levels, consistent with an effect on proteasomal degradation. However, this effect is strongly dependent upon the interaction of SGTA with the proteasomal component Rpn13. Hence, overexpression of the SGTA-binding region of Rpn13 or point mutations within the SGTA TPR domain both inhibit SGTA binding to the proteasome and substantially reduce MLP levels. These findings suggest that SGTA can regulate the access of MLPs to the proteolytic core of the proteasome, implying that a protein quality control cycle that involves SGTA and the BAG6 complex can operate at the 19S regulatory particle. We speculate that the binding of SGTA to Rpn13 enables specific polypeptides to escape proteasomal degradation and/or selectively modulates substrate degradation.
  • SGTA interacts with the proteasomal ubiquitin receptor Rpn13 via a carboxylate clamp mechanism

    Thapaliya, A.; Nyathi, Yvonne; Martínez-Lumbreras, S.; Krysztofinska, E.M.; Evans, N.J.; Terry, I.L.; High, S.; Isaacson, R.L. (2016-11)
    The fate of secretory and membrane proteins that mislocalize to the cytosol is decided by a collaboration between cochaperone SGTA (small, glutamine-rich, tetratricopeptide repeat protein alpha) and the BAG6 complex, whose operation relies on multiple transient and subtly discriminated interactions with diverse binding partners. These include chaperones, membrane-targeting proteins and ubiquitination enzymes. Recently a direct interaction was discovered between SGTA and the proteasome, mediated by the intrinsic proteasomal ubiquitin receptor Rpn13. Here, we structurally and biophysically characterize this binding and identify a region of the Rpn13 C-terminal domain that is necessary and sufficient to facilitate it. We show that the contact occurs through a carboxylate clamp-mediated molecular recognition event with the TPR domain of SGTA, and provide evidence that the interaction can mediate the association of Rpn13 and SGTA in a cellular context.
  • Structural complexity of the co-chaperone SGTA: a conserved C-terminal region is implicated in dimerization and substrate quality control

    Martínez-Lumbreras, S.; Krysztofinska, E.M.; Thapaliya, A.; Spilotros, A.; Matak-Vinkovic, D.; Salvadori, E.; Roboti, P.; Nyathi, Yvonne; Muench, J.H.; Roessler, M.M.; et al. (2018-07-11)
    Protein quality control mechanisms are essential for cell health and involve delivery of proteins to specific cellular compartments for recycling or degradation. In particular, stray hydrophobic proteins are captured in the aqueous cytosol by a co-chaperone, the small glutamine-rich, tetratricopeptide repeat-containing protein alpha (SGTA), which facilitates the correct targeting of tail-anchored membrane proteins, as well as the sorting of membrane and secretory proteins that mislocalize to the cytosol and endoplasmic reticulum-associated degradation. Full-length SGTA has an unusual elongated dimeric structure that has, until now, evaded detailed structural analysis. The Cterminal region of SGTA plays a key role in binding a broad range of hydrophobic substrates, yet in contrast to the well-characterized N-terminal and TPR domains, there is a lack of structural information on the C-terminal domain. In this study, we present new insights into the conformation and organization of distinct domains of SGTA and show that the C-terminal domain possesses a conserved region essential for substrate processing in vivo. We show that the C-terminal domain region is characterized by α-helical propensity and an intrinsic ability to dimerize independently of the N-terminal domain. Based on the properties of different regions of SGTA that are revealed using cell biology, NMR, SAXS, Native MS, and EPR, we observe that its C-terminal domain can dimerize in the full-length protein and propose that this reflects a closed conformation of the substrate-binding domain. Our results provide novel insights into the structural complexity of SGTA and provide a new basis for mechanistic studies of substrate binding and release at the C-terminal region.
  • Temporal rate is not a distinct perceptual metric.

    Motala, A.; Heron, James; McGraw, P.V.; Roach, N.W.; Whitaker, D. (2020-05)
    Sensory adaptation experiments have revealed the existence of ‘rate after-effects’ - adapting to a relatively fast rate makes an intermediate test rate feel slow, and adapting to a slow rate makes the same moderate test rate feel fast. The present work aims to deconstruct the concept of rate and clarify how exactly the brain processes a regular sequence of sensory signals. We ask whether rate forms a distinct perceptual metric, or whether it is simply the perceptual aggregate of the intervals between its component signals. Subjects were exposed to auditory or visual temporal rates (a ‘slow’ rate of 1.5 Hz and a ‘fast’ rate of 6 Hz), before being tested with single unfilled intervals of varying durations. Results show adapting to a given rate strongly influences the perceived duration of a single empty interval. This effect is robust across both interval reproduction and duration discrimination judgments. These findings challenge our understanding of rate perception. Specifically, they suggest that contrary to some previous assertions, the perception of sequence rate is strongly influenced by the perception of the sequence’s component duration intervals.
  • TfOH-catalyzed reaction of bispropargyl alcohols with 1,3-dicarbonyl compounds

    Teng, Q.; Mo, S.; Pan, J.; Wu, Na (Anna); Wang, H.; Pan, Y. (2016)
    A transition-metal-free efficient method for the preparation of 1,2,3-trisubstituted benzenes from bispropargyl alcohols and 1,3-dicarbonyl compounds has been developed. The reaction of bispropargyl alcohol with 1,3-dicarbonyl compound proceeds through [3,3]-rearrangement, 6π-electrocyclization, and unexpected Csp3−Csp2 regioselective σ-bond cleavage processes.
  • Service improvement in public sector operations - A European comparative analysis

    Breen, Liz; Hannibal, C.; Huaccho Huatuco, L.; Dehe, B.; Xie, Y. (Elsevier, 2020-06)
    Public sector state funded organisations were initially constructed to deliver much needed services to their immediate community. Designed to meet the needs of societies and populations, public sector operations focussed originally on the provision of health, welfare and social services, which were often free at the point of delivery or incurred a nominal charge. Today the effectiveness of public sector service organisations is constantly challenged and threatened by factors such as funding cuts, austerity measures, competition from private providers and political changes (e.g. the departure of the UK from the European Union and the shrinking of the state in many countries). With a focus on public sector efficiency and economic gains, the boundaries between public and private operations are becoming increasingly blurred, fuzzy and complex. To maintain economically sustainable services, public providers need to become more strategic, transparent and innovative in their decision-making, funds allocation and expenditure, workforce development and operations management, whilst acting in an ethical and responsible manner to maintain public confidence and trust.
  • A nordehydroabietyl amide-containing chiral diene for rhodium-catalysed asymmetric arylation to nitroolefins

    Li, R.; Wen, Z.; Wu, Na (Anna) (2016-12)
    A highly enantioselective rhodium catalysed asymmetric arylation (RCAA) of nitroolefins with arylboronic acids is presented using a newly developed, C1-symmetric, non-covalent interacted, phellandrene derived, nordehydroabietyl amide-containing chiral diene under mild conditions. Stereoelectronic effects were studied, suggesting an activation of the bound substrate through the secondary amide as a hydrogen-bond donor.
  • Atom-economical chemoselective synthesis of furocoumarins via cascade palladium catalyzed oxidative aloxylation of 4-oxohydrocoumarins and alkenes

    Tan, X.; Zhao, H.; Pan, Y.; Wu, Na (Anna); Wang, H.; Chen, Z. (2015-01)
    A novel and efficient procedure for the synthesis of furo[3,2-c] coumarins from readily available 4-oxohydrocoumarins and alkenes in the presence of a catalytic amount of Pd(CF3COO)2 has been developed. Atom-economical characteristics and mild conditions of this method are in accord with the concept of modern green chemistry.
  • 1,4‐Addition of TMSCCl3 to nitroalkenes: efficient reaction conditions and mechanistic understanding

    Wu, Na (Anna); Wahl, B.; Woodward, S.; Lewis, W. (2014-06)
    Improved synthetic conditions allow preparation of TMSCCl3 in good yield (70 %) and excellent purity. Compounds of the type NBu4X [X=Ph3SiF2 (TBAT), F (tetrabutylammonium fluoride, TBAF), OAc, Cl and Br] act as catalytic promoters for 1,4‐additions to a range of cyclic and acyclic nitroalkenes, in THF at 0–25 °C, typically in moderate to excellent yields (37–95 %). TBAT is the most effective promoter and bromide the least effective. Multinuclear NMR studies (1H, 19F, 13C and 29Si) under anaerobic conditions indicate that addition of TMSCCl3 to TBAT (both 0.13 M ) at −20 °C, in the absence of nitroalkene, leads immediately to mixtures of Me3SiF, Ph3SiF and NBu4CCl3. The latter is stable to at least 0 °C and does not add nitroalkene from −20 to 0 °C, even after extended periods. Nitroalkene, in the presence of TMSCCl3 (both 0.13 M at −20 °C), when treated with TBAT, leads to immediate formation of the 1,4‐addition product, suggesting the reaction proceeds via a transient [Me3Si(alkene)CCl3] species, in which (alkene) indicates an Si⋅⋅⋅O coordinated nitroalkene. The anaerobic catalytic chain is propagated through the kinetic nitronate anion resulting from 1,4 CCl3− addition to the nitroalkene. This is demonstrated by the fact that isolated NBu4[CH2=NO2] is an efficient promoter. Use of H2C=CH(CH2)2CH=CHNO2 in air affords radical‐derived bicyclic products arising from aerobic oxidation.

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