• Beyond the grave: human remains from domestic contexts in Atlantic Scotland

      Armit, Ian; Ginn, V. (2007)
      The occurrence of human remains in Iron Age domestic contexts in southern England is well-attested and has been the subject of considerable recent debate. Less well known are the human remains from settlement contexts in other parts of Iron Age Britain. In Atlantic Scotland, human bodies and body parts are found consistently, if in small numbers, in Atlantic roundhouses, wheelhouses, and other settlement forms. Yet these have remained unsynthesised and individual assemblages have tended to be interpreted on a site-specific basis, if at all. Examination of the material as a corpus suggests a complex and evolving set of attitudes to the human body, its display, curation, and disposal, and it is improbable that any single interpretation (such as excarnation, retention of war trophies, or display of ancestral relics) will be sufficient. Although the specific practices remain diverse and essentially local, certain concerns appear common to wider areas, and some, for instance the special treatment accorded to the head, have resonances far beyond Iron Age Britain.
    • Biallelic Mutations in the Autophagy Regulator DRAM2 Cause Retinal Dystrophy with Early Macular Involvement

      El-Asrag, M.E.; Sergouniotis, P.I.; McKibbin, M.; Plagnol, V.; Sheridan, E.; Waseem, N.; Abdelhamed, Z.; McKeefry, Declan J.; Van Schil, K.; Poulter, J.A.; et al. (2015-06)
      Retinal dystrophies are an overlapping group of genetically heterogeneous conditions resulting from mutations in more than 250 genes. Here we describe five families affected by an adult-onset retinal dystrophy with early macular involvement and associated central visual loss in the third or fourth decade of life. Affected individuals were found to harbor disease-causing variants in DRAM2 (DNA-damage regulated autophagy modulator protein 2). Homozygosity mapping and exome sequencing in a large, consanguineous British family of Pakistani origin revealed a homozygous frameshift variant (c.140delG [p.Gly47Valfs∗3]) in nine affected family members. Sanger sequencing of DRAM2 in 322 unrelated probands with retinal dystrophy revealed one European subject with compound heterozygous DRAM2 changes (c.494G>A [p.Trp165∗] and c.131G>A [p.Ser44Asn]). Inspection of previously generated exome sequencing data in unsolved retinal dystrophy cases identified a homozygous variant in an individual of Indian origin (c.64_66del [p.Ala22del]). Independently, a gene-based case-control association study was conducted via an exome sequencing dataset of 18 phenotypically similar case subjects and 1,917 control subjects. Using a recessive model and a binomial test for rare, presumed biallelic, variants, we found DRAM2 to be the most statistically enriched gene; one subject was a homozygote (c.362A>T [p.His121Leu]) and another a compound heterozygote (c.79T>C [p.Tyr27His] and c.217_225del [p.Val73_Tyr75del]). DRAM2 encodes a transmembrane lysosomal protein thought to play a role in the initiation of autophagy. Immunohistochemical analysis showed DRAM2 localization to photoreceptor inner segments and to the apical surface of retinal pigment epithelial cells where it might be involved in the process of photoreceptor renewal and recycling to preserve visual function.
    • Biarylpyrimidines: a new class of ligand for high-order DNA recognition

      Murphy, Peter M.; Phillips, Victoria A.; Jennings, Sharon A.; Garbett, N.C.; Chaires, J.B.; Jenkins, Terence C.; Wheelhouse, Richard T. (2003)
      Biarylpyrimidines bearing ω-aminoalkyl substituents have been designed as ligands for high-order DNA structures: spectrophotometric, thermal and competition equilibrium dialysis assays showed that changing the functional group for substituent attachment from thioether to amide switches the structural binding preference from triplex to tetraplex DNA; the novel ligands are non-toxic and moderate inhibitors of human telomerase.
    • Bias effects of short- and long-term color memory for unique objects

      Bloj, Marina; Weiß, D.; Gegenfurtner, K.R. (2016-03-09)
      Are objects remembered with a more saturated color? Some of the evidence supporting this statement comes from research using “memory colors”—the typical colors of particular objects, for example, the green of grass. The problematic aspect of these findings is that many different exemplars exist, some of which might exhibit a higher saturation than the one measured by the experimenter. Here we avoid this problem by using unique personal items and comparing long- and short-term color memory matches (in hue, value, and chroma) with those obtained with the object present. Our results, on average, confirm that objects are remembered as more saturated than they are.
    • The big green lab project

      Lucas, Beverley J.; Comerford Boyes, Louise; Karodia, Nazira; Munshi, Tasnim; Martin, William H.C.; Hopkinson, Peter G. (2014-03)
      Beverley Lucas and her colleagues give us a big green welcome to the Ecoversity of Bradford In 2005, the Higher Education Funding Council for England (Hefce) stated that ‘the greatest contribution a university can make to sustainable development is through the education of their graduates’. The University of Bradford took up the gauntlet, embedding sustainable development in all areas of its campus whilst also transforming the curriculum across the university to educate for sustainable development. This led to them coining themselves an ecoversity.
    • Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling

      Kickstein, E.; Krauss, S.; Thornhill, P.; Rutschow, D.; Zeller, R.; Sharkey, J.; Williamson, Ritchie; Fuchs, M.; Kohler, A.; Glossmann, H.; et al. (2010)
      Hyperphosphorylated tau plays an important role in the formation of neurofibrillary tangles in brains of patients with Alzheimer's disease (AD) and related tauopathies and is a crucial factor in the pathogenesis of these disorders. Though diverse kinases have been implicated in tau phosphorylation, protein phosphatase 2A (PP2A) seems to be the major tau phosphatase. Using murine primary neurons from wild-type and human tau transgenic mice, we show that the antidiabetic drug metformin induces PP2A activity and reduces tau phosphorylation at PP2A-dependent epitopes in vitro and in vivo. This tau dephosphorylating potency can be blocked entirely by the PP2A inhibitors okadaic acid and fostriecin, confirming that PP2A is an important mediator of the observed effects. Surprisingly, metformin effects on PP2A activity and tau phosphorylation seem to be independent of AMPK activation, because in our experiments (i) metformin induces PP2A activity before and at lower levels than AMPK activity and (ii) the AMPK activator AICAR does not influence the phosphorylation of tau at the sites analyzed. Affinity chromatography and immunoprecipitation experiments together with PP2A activity assays indicate that metformin interferes with the association of the catalytic subunit of PP2A (PP2Ac) to the so-called MID1-alpha4 protein complex, which regulates the degradation of PP2Ac and thereby influences PP2A activity. In summary, our data suggest a potential beneficial role of biguanides such as metformin in the prophylaxis and/or therapy of AD.
    • Binding affinities of amino acid analogues at the charged aqueous titania interface: implications for titania-binding peptides

      Sultan, A.M.; Hughes, Zak E.; Walsh, T.R. (2014-11)
      Despite the extensive utilization of biomolecule-titania interfaces, biomolecular recognition and interactions at the aqueous titania interface remain far from being fully understood. Here, atomistic molecular dynamics simulations, in partnership with metadynamics, are used to calculate the free energy of adsorption of different amino acid side chain analogues at the negatively-charged aqueous rutile TiO2 (110) interface, under conditions corresponding with neutral pH. Our calculations predict that charged amino acid analogues have a relatively high affinity to the titania surface, with the arginine analogue predicted to be the strongest binder. Interactions between uncharged amino acid analogues and titania are found to be repulsive or weak at best. All of the residues that bound to the negatively-charged interface show a relatively stronger adsorption compared with the charge-neutral interface, including the negatively-charged analogue. Of the analogues that are found to bind to the titania surface, the rank ordering of the binding affinities is predicted to be "arginine" > "lysine" ≈ aspartic acid > "serine". This is the same ordering as was found previously for the charge-neutral aqueous titania interface. Our results show very good agreement with available experimental data and can provide a baseline for the interpretation of peptide-TiO2 adsorption data.
    • Binding of bacteria to poly (N-isopropylacrylamide) modified with vancomycin: Comparison of behavior of linear and highly branched polymers

      Teratanatorn, P.; Hoskins, Richard; Swift, Thomas; Douglas, C.W.I.; Shepherd, J.; Rimmer, Stephen (2017)
      The behavior of a linear copolymer of N-isopropyl acrylamide with pendant vancomycin functionality was compared to an analogous highly branched copolymer with vancomycin functionality at the chain ends. Highly branched poly(N-isopropylacrylamide) modified with vancomycin (HB-PNIPAM-van) was synthesized by functionalization of the HB-PNIPAM, prepared using reversible addition-fragmentation chain transfer polymerization. Linear PNIPAM with pendant vancomycin functionality (L-PNIPAM-van) was synthesized by functionalization of poly(N-isopropyl acrylamide-co-vinyl benzoic acid). HB-PNIPAM-van aggregated S. aureus effectively whereas the L-PNIPAM-van polymer did not. It was found that when the HB-PNIPAM-van was incubated with S. aureus the resultant phase transition provided an increase in the intensity of fluorescence of a solvatochromic dye, nile red, added to the system. In contrast, a significantly lower increase in fluorescence intensity was obtained when L-PNIPAM-van was incubated with S. aureus. These data showed that the degree of desolvation of HB-PNIPAM-van was much greater than the desolvation of the linear version. Using microCalorimetry it was shown that there were no significant differences in the affinities of the polymer ligands for D-Ala-D-Ala and therefore differences in the interactions with bacteria were associated with changes in the probability of access of the polymer bound ligands to the D-Ala-D-Ala dipeptide. The data support the hypothesis that generation of polymer systems that respond to cellular targets, for applications such as cell targeting, detection of pathogens etc., requires the use of branched polymers with ligands situated at the chain ends.
    • 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.
    • Binge eating, disinhibition and obesity

      Ulijaszek, S.; Bryant, Eleanor J. (2016)
      Obese individuals, especially those who are morbidly obese, are more likely to binge-eat and to have Disinhibition, as measured by the Three Factor Eating Questionnaire of Stunkard and Messick (1985). The latter characterises very opportunistic eating behaviour and signifies a readiness to eat. We argue in this chapter that binge eating and Disinhibition are deeply adaptive as mechanisms for dealing with one of the most fundamental of insecurities, that of food, especially in seasonal and unpredictable environments. It is only in recent decades, with improved food security in industrialized nations and the emergence of obesity at the population level, that they have become maladaptive in terms of health outcomes, and have been medically pathologized. Binge-eating and Disinhibition are no longer responses to uncertainty in food availability has they would have been in the evolutionary past. Rather, there may be other types of uncertainty and insecurity that lead to Disinhibition, binge-eating and obesity, and clinical practice should perhaps turn to examining these as higher-level factors that structure health and illness. These would include stress at work and in everyday life
    • Binocular correlation of ocular aberration dynamics

      Chin, Sem Sem; Hampson, Karen M.; Mallen, Edward A.H. (2008)
      Fluctuations in accommodation have been shown to be correlated in the two eyes of the same subject. However, the dynamic correlation of higher-order aberrations in the frequency domain has not been studied previously. A binocular Shack-Hartmann wavefront sensor is used to measure the ocular wavefront aberrations concurrently in both eyes of six subjects at a sampling rate of 20.5 Hz. Coherence function analysis shows that the inter-ocular correlation between aberrations depends on subject, Zernike mode and frequency. For each subject, the coherence values are generally low across the resolvable frequency range (mean 0.11), indicating poor dynamic correlation between the aberrations of the two eyes. Further analysis showed that phase consistency dominates the coherence values. Monocular and binocular viewing conditions showed similar power spectral density functions.
    • Binocular summation and other forms of non-dominant eye contribution in individuals with strabismic amblyopia during habitual viewing

      Barrett, Brendan T.; Panesar, Gurvinder K.; Scally, Andy J.; Pacey, Ian E. (2013-10-29)
      Adults with amblyopia ('lazy eye'), long-standing strabismus (ocular misalignment) or both typically do not experience visual symptoms because the signal from weaker eye is given less weight than the signal from its fellow. Here we examine the contribution of the weaker eye of individuals with strabismus and amblyopia with both eyes open and with the deviating eye in its anomalous motor position. The task consisted of a blue-on-yellow detection task along a horizontal line across the central 50 degrees of the visual field. We compare the results obtained in ten individuals with strabismic amblyopia with ten visual normals. At each field location in each participant, we examined how the sensitivity exhibited under binocular conditions compared with sensitivity from four predictions, (i) a model of binocular summation, (ii) the average of the monocular sensitivities, (iii) dominant-eye sensitivity or (iv) non-dominant-eye sensitivity. The proportion of field locations for which the binocular summation model provided the best description of binocular sensitivity was similar in normals (50.6%) and amblyopes (48.2%). Average monocular sensitivity matched binocular sensitivity in 14.1% of amblyopes' field locations compared to 8.8% of normals'. Dominant-eye sensitivity explained sensitivity at 27.1% of field locations in amblyopes but 21.2% in normals. Non-dominant-eye sensitivity explained sensitivity at 10.6% of field locations in amblyopes but 19.4% in normals. Binocular summation provided the best description of the sensitivity profile in 6/10 amblyopes compared to 7/10 of normals. In three amblyopes, dominant-eye sensitivity most closely reflected binocular sensitivity (compared to two normals) and in the remaining amblyope, binocular sensitivity approximated to an average of the monocular sensitivities. Our results suggest a strong positive contribution in habitual viewing from the non-dominant eye in strabismic amblyopes. This is consistent with evidence from other sources that binocular mechanisms are frequently intact in strabismic and amblyopic individuals.
    • A Bioarchaeological Study of Medieval Burials on the Site of St Mary Spital: Excavations at Spitalfields Market, London E1, 1991–2007.

      Buckberry, Jo (2015-03)
      I have been eagerly awaiting the publication of this book since 2000, when, as a PhD student, I was lucky enough to be able to visit the St Mary Spital excavations where I knew quite a few of the excavators and osteologists. It was apparent at that early stage in the research of St Mary Spital that this was a very exciting and important excavation and skeletal assemblage. This book does not disappoint.
    • Biocatalytic Amide Condensation and Gelation Controlled by Light

      Sahoo, J.K.; Nalluri, S.K.M.; Javid, Nadeem; Webb, H.; Ulijn, R.V. (2014-03-25)
      We report on a supramolecular self-assembly system that displays coupled light switching, biocatalytic condensation/hydrolysis and gelation. The equilibrium state of this system can be regulated by light, favouring in situ formation, by protease catalysed peptide synthesis, of self-assembling trans-Azo-YF-NH2 in ambient light; however, irradiation with UV light gives rise to the cis-isomer, which readily hydrolyzes to its amino acid derivatives (cis-Azo-Y + F-NH2) with consequent gel dissolution.
    • Biocatalytic production of bicyclic β-lactams with three contiguous chiral centres using engineered crotonases

      Hamed, Refaat B.; Gomez-Castellanos, J.R.; Warhaut, H.L.; Claridge, T.D.W.; Schofield, C.J. (2019-01-24)
      There is a need to develop asymmetric routes to functionalised β-lactams, which remain the most important group of antibacterials. Here we describe biocatalytic and protein engineering studies concerning carbapenem biosynthesis enzymes, aiming to enable stereoselective production of functionalised carbapenams with three contiguous chiral centres. Structurallyguided substitutions of wildtype carboxymethylproline synthases enable tuning of their C-N and C-C bond forming capacity to produce 5-carboxymethylproline derivatives substituted at C-4 and C-6, from amino acid aldehyde and malonyl-CoA derivatives. Use of tandem enzyme incubations comprising an engineered carboxymethylproline synthase and an alkylmalonylCoA forming enzyme (i.e. malonyl-CoA synthetase or crotonyl-CoA carboxylase reductase) can improve stereocontrol and expand the product range. Some of the prepared 4,6-disubstituted-5-carboxymethylproline derivatives are converted to bicyclic β-lactams by carbapenam synthetase catalysis. The results illustrate the utility of tandem enzyme systems involving engineered crotonases for asymmetric bicyclic β-lactam synthesis.
    • Biocatalytic Self-Assembly of Supramolecular Charge Transfer Nanostructures Based on n-Type Semiconductor-Appended Peptide

      Nalluri, S.K.M.; Berdugo, C.; Javid, Nadeem; Frederix, P.W.J.M.; Ulijn, R.V. (2014-05-30)
      The reversible in situ formation of a self-assembly building block (naphthalenediimide (NDI)–dipeptide conjugate) by enzymatic condensation of NDI-functionalized tyrosine (NDI-Y) and phenylalanine-amide (F-NH2) to form NDI-YF-NH2 is described. This coupled biocatalytic condensation/assembly approach is thermodynamically driven and gives rise to nanostructures with optimized supramolecular interactions as evidenced by substantial aggregation induced emission upon assembly. Furthermore, in the presence of di-hydroxy/alkoxy naphthalene donors, efficient charge-transfer complexes are produced. The dynamic formation of NDI-YF-NH2 and electronic and H-bonding interactions are analyzed and characterized by different methods. Microscopy (TEM and AFM) and rheology are used to characterize the formed nanostructures. Dynamic nanostructures, whose formation and function are driven by free-energy minimization, are inherently self-healing and provide opportunities for the development of aqueous adaptive nanotechnology.
    • Biocatalytically Triggered Co‐Assembly of Two‐Component Core/Shell Nanofibers

      Abul-Haija, Y.M.; Roy, S.; Frederix, P.W.J.M.; Javid, Nadeem; Jayawarna, V.; Ulijn, R.V. (2014-03-05)
      For the development of applications and novel uses for peptide nanostructures, robust routes for their surface functionalization, that ideally do not interfere with their self‐assembly properties, are required. Many existing methods rely on covalent functionalization, where building blocks are appended with functional groups, either pre‐ or post‐assembly. A facile supramolecular approach is demonstrated for the formation of functionalized nanofibers by combining the advantages of biocatalytic self‐assembly and surfactant/gelator co‐assembly. This is achieved by enzymatically triggered reconfiguration of free flowing micellar aggregates of pre‐gelators and functional surfactants to form nanofibers that incorporate and display the surfactants’ functionality at the surface. Furthermore, by varying enzyme concentration, the gel stiffness and supramolecular organization of building blocks can be varied.
    • Bioflavonoid coated materials

      Thomas, Howard; Dowling, D.P.; Katsikogianni, Maria G. (2014)
      Polymeric materials are described which have a bioflavonoid coating, the bioflavonoid content of the coating comprising at least naringin and neohesperidin. The use of such coated polymeric materials is also described as well as the process for making the coated polymeric materials.
    • Bioinformatic insights into the biosynthesis of the Group B carbohydrate in Streptococcus agalactiae

      Sutcliffe, I.C.; Black, G.W.; Harrington, Dean J. (2008-05-01)
      Streptococcus agalactiae is a major human and animal pathogen, most notable as a cause of life-threatening disease in neonates. S. agalactiae is also called the Group B Streptococcus in reference to the diagnostically significant Lancefield Group B typing antigen. Although the structure of this complex carbohydrate antigen has been solved, little is known of its biosynthesis beyond the identification of a relevant locus in sequenced S. agalactiae genomes. Analysis of the sugar linkages present in the Group B carbohydrate (GBC) structure has allowed us to deduce the minimum enzymology required to complete its biosynthesis. Most of the enzymes required to complete this biosynthesis can be identified within the putative biosynthetic locus. Surprisingly, however, three crucial N-acetylglucosamine transferases and enzymes required for activated precursor synthesis are not apparently located in this locus. A model for GBC biosynthesis wherein the complete polymer is assembled at the cytoplasmic face of the plasma membrane before translocation to the cell surface is proposed. These analyses also suggest that GBC is the major teichoic acid-like polymer in the cell wall of S. agalactiae, whereas lipoteichoic acid is the dominant poly(glycerophosphate) antigen. Genomic analysis has allowed us to predict the pathway leading to the biosynthesis of GBC of S. agalactiae.