• P.C. Ray: Student days in Edinburgh

      Wright, Colin W.; Alexander, A.J. (2016)
    • p53/p63/p73 in the Epidermis in Health and Disease

      Botchkarev, Vladimir A.; Flores, E.R. (2014)
      Although p53 has long been known as the “guardian of the genome” with a role in tumor suppression in many tissues, the discovery of two p53 ancestral genes, p63 and p73, more than a decade ago has triggered a considerable amount of research into the role of these genes in skin development and diseases. In this review, we primarily focus on mechanisms of action of p53 and p63, which are the best-studied p53 family members in the skin. The existence of multiple isoforms and their roles as transcriptional activators and repressors are key to their function in multiple biological processes including the control of skin morphogenesis, regeneration, tumorigenesis, and response to chemotherapy. Last, we provide directions for further research on this family of genes in skin biology and pathology.
    • p63 and Brg1 control developmentally regulated higher-order chromatin remodelling at the epidermal differentiation complex locus in epidermal progenitor cells

      Mardaryev, Andrei N.; Gdula, Michal R.; Yarker, Joanne L.; Emelianov, V.U.; Poterlowicz, Krzysztof; Sharov, A.A.; Sharova, T.Y.; Scarpa, J.A.; Chambon, P.; Botchkarev, Vladimir A.; et al. (2014)
    • p63 regulates Satb1 to control tissue-specific chromatin remodeling during development of the epidermis

      Fessing, Michael Y.; Mardaryev, Andrei N.; Gdula, Michal R.; Sharov, A.A.; Sharova, T.Y.; Rapisarda, Valentina; Gordon, K.B.; Smorodchenko, A.D.; Poterlowicz, Krzysztof; Ferone, G.; et al. (2011)
      During development, multipotent progenitor cells establish tissue-specific programs of gene expression. In this paper, we show that p63 transcription factor, a master regulator of epidermal morphogenesis, executes its function in part by directly regulating expression of the genome organizer Satb1 in progenitor cells. p63 binds to a proximal regulatory region of the Satb1 gene, and p63 ablation results in marked reduction in the Satb1 expression levels in the epidermis. Satb1(-/-) mice show impaired epidermal morphology. In Satb1-null epidermis, chromatin architecture of the epidermal differentiation complex locus containing genes associated with epidermal differentiation is altered primarily at its central domain, where Satb1 binding was confirmed by chromatin immunoprecipitation-on-chip analysis. Furthermore, genes within this domain fail to be properly activated upon terminal differentiation. Satb1 expression in p63(+/-) skin explants treated with p63 small interfering ribonucleic acid partially restored the epidermal phenotype of p63-deficient mice. These data provide a novel mechanism by which Satb1, a direct downstream target of p63, contributes in epidermal morphogenesis via establishing tissue-specific chromatin organization and gene expression in epidermal progenitor cells.
    • p63 transcription factor regulates nuclear shape and expression of nuclear envelope-associated genes in epidermal keratinocyte

      Rapisarda, Valentina; Malashchuk, Igor; Asamaowei, Inemo E.; Poterlowicz, Krzysztof; Fessing, Michael Y.; Sharov, A.A.; Karakesisoglou, I.; Botchkarev, Vladimir A.; Mardaryev, Andrei N. (2017)
      The maintenance of a proper nuclear architecture and 3D organization of the genes, enhancer elements and transcription machinery plays an essential role in tissue development and regeneration. Here we show that in the developing skin, epidermal progenitor cells of mice lacking p63 transcription factor display alterations in the nuclear shape accompanied by marked decrease in expression of several nuclear envelop-associated components (Lamin B1, Lamin A/C, SUN1, Nesprin-3, Plectin) compared to controls. Furthermore, ChIP-qPCR assay showed enrichment of p63 on Sun1, Syne3 and Plec promoters, suggesting them as p63 targets. Alterations in the nuclei shape and expression of nuclear envelope-associated proteins were accompanied by altered distribution patterns of the repressive histone marks H3K27me3, H3K9me3 and heterochromatin protein 1- alpha in p63-null keratinocytes. These changes were also accompanied by downregulation of the transcriptional activity and relocation of the keratinocyte-specific gene loci away from the sites of active transcription towards the heterochromatin-enriched repressive nuclear compartments in p63-null cells. These data demonstrate functional links between the nuclear envelope organization, chromatin architecture and gene expression in keratinocytes and suggest nuclear envelope-associated genes as important targets mediating p63-regulated gene expression programme in the epidermis.
    • Palaeoenvironmental reconstruction: evidence for seasonality at Allia Bay, Kenya, at 3.9 million years

      Macho, Gabriele A.; Jiang, Y.; Leakey, M.G.; Williamson, D.K. (2003)
      In an earlier study, stress lines in primate teeth were found to occur on a recurrent basis, probably corresponding to seasonal fluctuations in environmental parameters, such as food availability (Macho et al., J. Hum. Evol. 30 (1996) 57¿70). In the present study this approach was extended to the study of teeth of extant and extinct mammals, with the specific aim to determine the pattern of seasonality at the Australopithecus anamensis-bearing site at Allia Bay, Kenya. It was found that extant and extinct species, who share similar dietary/ecological adaptations, are comparable in their patterns of stress. Typical browsers/mixed feeders were found to exhibit three recurrent disturbances per year, whereas grazers usually only exhibit two. The average spacing between lines is also comparable between extant and extinct species. Hence, while the severity and predictability of the seasons probably fluctuated during crucial periods of hominin evolution, there is little doubt that all hominins lived in a seasonal environment. At Allia Bay, the pattern of stress lines found in mammals suggests that the environmental conditions in which A. anamensis lived may have been comparable to those found in the Masai Mara today.
    • 'Palaeoshellomics' reveals the use of freshwater mother-of-pearl in prehistory

      Sakalauskaite, J.; Andersen, S.H.; Biagi, P.; Borrello, M.A.; Cocquerez, T.; Colonese, A.C.; Bello, F.D.; Girod, A.; Heumuller, M.; Koon, Hannah E.C.; et al. (2019-05)
      The extensive use of mollusc shell as a versatile raw material is testament to its importance in prehistoric times. The consistent choice of certain species for different purposes, including the making of ornaments, is a direct representation of how humans viewed and exploited their environment. The necessary taxonomic information, however, is often impossible to obtain from objects that are small, heavily worked or degraded. Here we propose a novel biogeochemical approach to track the biological origin of prehistoric mollusc shell. We conducted an in-depth study of archaeological ornaments using microstructural, geochemical and biomolecular analyses, including ‘palaeoshellomics’, the first application of palaeoproteomics to mollusc shells (and indeed to any invertebrate calcified tissue). We reveal the consistent use of locally-sourced freshwater mother-of-pearl for the standardized manufacture of ‘double-buttons’. This craft is found throughout Europe between 4200–3800 BCE, highlighting the ornament-makers’ profound knowledge of the biogeosphere and the existence of cross-cultural traditions.
    • Palladium-catalysed ligand-free reductive Heck cycloisomerisation of 1,6-en-α-chloro-enamides

      Hou, Y.; Ma, J.; Yang, H.; Anderson, E.A.; Whiting, A.; Wu, Na (Anna) (2019-03)
      The first example of an intramolecular hydroarylation of 1,6-en-α-chloro-enamides was achieved by a palladium-catalysed ligand-free reductive Heck cycloisomerisation with no competing Heck-cyclised by-product.
    • Palynology, phytoliths, diatoms and wood in the West Mouth: stratigraphic and taphonomic studies of Late Quaternary vegetation history

      Hunt, C.; Kealhofer, L.; Premathilake, R.; Rushworth, Garry; Gilbertson, D.; Jones, S.; Thompson, Gill B. (2016)
    • Pandoraea sp. strain E26: discovery of its quorum-sensing properties via whole-genome sequence analysis

      Chan, K; Yin, W.; Tee, K.K.; Chang, Chien-Yi; Priya, K. (2015-05)
      We report the draft genome sequence of Pandoraea sp. strain E26 isolated from a former landfill site, sequenced by the Illumina MiSeq platform. This genome sequence will be useful to further understand the quorum-sensing system of this isolate.
    • Papain-catalysed mechanochemical synthesis of oligopeptides by milling and twin-screw extrusion: application in the Juliá-Colonna enantioselective epoxidation

      Ardila-Fierro, K.; Crawford, Deborah E.; Körner, A.; James, S.L.; Bolm, C.; Hernández, J.G. (2018-01)
      The oligomerisation of L-amino acids by papain was studied in a mixer ball mill and in a planetary ball mill. The biocatalyst proved stable under the ball milling conditions providing the corresponding oligopeptides in good to excellent yields and with a variable degree of polymerisation. Both parameters were found to be dependent on the reaction conditions and on the nature of the amino acid (specifically on its side-chain size and hydrophobicity). In addition, the chemoenzymatic oligomerisation was demonstrated by utilising twin-screw extrusion technology, which allowed for a scalable continuous process. Finally, the synthesised oligo(L-Leu) 2b proved to be active as a catalyst in the Juliá–Colonna enantioselective epoxidation of chalcone derivatives.
    • Parallel evaluation of Doxorubicin inducing Genetic damage in human lymphocytes and sperm using the Comet assay and spectral karyotyping

      Anderson, Diana; Baumgartner, Adolf; Cemeli, Eduardo; Schmid, Thomas E. (2004)
      In recent years, two techniques for detecting genetic damage in the whole genome have gained importance: the alkaline comet assay, to detect DNA damage such as strand breaks and alkali-labile sites, and a multicolour FISH method, spectral karyotyping (SKY), to identify chromosomal aberrations simultaneously in all metaphase chromosomes. In the present study, the induction of DNA damage in human sperm and lymphocytes in vitro has been studied employing an anticancer drug, doxorubicin (DX). An increase in DNA damage was observed with the comet assay as the median per cent head DNA of sperm significantly decreased from 82.07 and 85.14% in the untreated control groups to 63.48 and 72.52% at doses of 0.8 µM DX. At 1.6 µM the percentage declined to 60.96% (the corresponding tail moment increased from 4.42 to 12.19). In stimulated lymphocytes, a significant increase was observed in tail moment, from 0.72 and 0.53 in controls to 15.17 and 12.10 at 0.2 µM DX, continuing at the same level to a final concentration of 1.6 µM. Structural aberrations found in the parallel SKY study in stimulated lymphocytes at 0.2 µM DX consisted of 14% chromatid-type and 2% chromosome-type aberrations; none were found in controls. The SKY results correlate very well with the findings of the comet assay in lymphocytes where DNA damage was observed at similar doses. This study is the first reporting use of the comet assay and SKY analysis in parallel after chemical treatment. The potential of the two techniques together is evident, as they represent a set of assays feasible for evaluating damage in human somatic and germ cells after chemical treatment (i) by direct observation of two different end-points, detecting general DNA damage and chromosomal aberrations and (ii) by extrapolation from lymphocytes to sperm, which provides a `parallelogram¿ approach in human cells.
    • Parallel RNA interference screens identify EGFR activation as an escape mechanism in FGFR3-mutant cancer

      Herrera-Abreu, M.T.; Pearson, A.; Campbell, J.; Shnyder, Steven D.; Knowles, M.A.; Ashworth, A.; Turner, N.C. (2013)
      Activation of fibroblast growth factor receptors (FGFR) is a common oncogenic event. Little is known about the determinants of sensitivity to FGFR inhibition and how these may vary between different oncogenic FGFRs. Using parallel RNA interference (RNAi) genetic screens, we show that the EGF receptor (EGFR) limits sensitivity to FGFR inhibition in FGFR3-mutant and -translocated cell lines, but not in other FGFR-driven cell lines. We also identify two distinct mechanisms through which EGFR limits sensitivity. In partially FGFR3-dependent lines, inhibition of FGFR3 results in transient downregulation of mitogen-activated protein kinase signaling that is rescued by rapid upregulation of EGFR signaling. In cell lines that are intrinsically resistant to FGFR inhibition, EGFR dominates signaling via repression of FGFR3, with EGFR inhibition rescued by delayed upregulation of FGFR3 expression. Importantly, combinations of FGFR and EGFR inhibitors overcome these resistance mechanisms in vitro and in vivo. Our results illustrate the power of parallel RNAi screens in identifying common resistance mechanisms to targeted therapies. SIGNIFICANCE: Our data identify a novel therapeutic approach to the treatment of FGFR3-mutant cancer, emphasizing the potential of combination approaches targeting both FGFR3 and EGFR. Our data extend the role of EGFR in mediating resistance to inhibitors targeting a mutant oncogene, showing that EGFR signaling can repress mutant FGFR3 to induce intrinsic resistance to FGFR targeting.
    • Part-time versus full-time occlusion therapy for treatment of amblyopia: A meta-analysis

      Yazdani, N.; Sadeghi, R.; Momeni-Moghaddam, H.; Zarifmahmoudi, L.; Ehsaei, Asieh; Barrett, Brendan T. (2017)
      Purpose: To compare full-time occlusion (FTO) and part-time occlusion (PTO) therapy in the treatment of amblyopia, with the secondary aim of evaluating the minimum number of hours of part-time patching required for maximal effect from occlusion. Methods: A literature search was performed in PubMed, Scopus, Science Direct, Ovid, Web of Science and Cochrane library. Methodological quality of the literature was evaluated according to the Oxford Center for Evidence Based Medicine and modified Newcastle-Ottawa scale. Statistical analyses were performed using Comprehensive Meta-Analysis (version 2, Biostat Inc., USA). Results: The present meta-analysis included six studies (three randomized controlled trials [RCTs] and three non-RCTs). Pooled standardized difference in the mean changes in the visual acuity was 0.337 [lower and upper limits: 0.009, 0.683] higher in the FTO as compared to the PTO group; however, this difference was not statistically significant (P ¼ 0.056, Cochrane Q value ¼ 20.4 (P ¼ 0.001), I2 ¼ 75.49%). Egger's regression intercept was 5.46 (P ¼ 0.04). The pooled standardized difference in means of visual acuity changes was 1.097 [lower and upper limits: 0.68, 1.513] higher in the FTO arm (P < 0.001), and 0.7 [lower and upper limits: 0.315, 1.085] higher in the PTO arm (P < 0.001) compared to PTO less than two hours. Conclusions: This meta-analysis shows no statistically significant difference between PTO and FTO in treatment of amblyopia. However, our results suggest that the minimum effective PTO duration, to observe maximal improvement in visual acuity is six hours per day.
    • Particle formation by mixing with supercritical antisolvent at high Reynolds numbers.

      Shekunov, Boris Yu.; Baldyga, J.; York, Peter (2001)
      A precipitation process is considered in which completely miscible solution and supercritical antisolvent are passed through premixing and diluting zones of a turbulent flow. The influence of flow velocity on particle size and nuclei concentration is discussed in terms of mixing and precipitation time constants and their supersaturation dependencies. The proposed model allowed the major process parameters such as supersaturation profile, mixed fluid fraction and mean particle size to be calculated and compared with experimental data. For the crystallization system paracetamol/ethanol/CO2 studied, the supersaturation profile becomes established at Re104. The particle size and shape are defined, firstly, by increase of supersaturation and relative volume of mixed (on molecular scale) fluid with increase of flow velocity and, secondly, by decrease of residence time available for nucleation with increase of flow velocity. These competitive processes can result in minimum particle size at a defined flow rate.
    • Partition of neutral molecules and ions from water to o-nitrophenyl octyl ether and of neutral molecules from the gas phase to o-nitrophenyl octyl ether

      Abraham, M.H.; Acree Jr, W.E.; Liu, Xiangli (2018-02)
      We have set out an equation for partition of 87 neutral molecules from water to o-nitrophenyl octyl ether, NPOE, an equation for partition of the 87 neutral molecules and 21 ionic species from water to NPOE, and an equation for partition of 87 neutral molecules from the gas phase to NPOE. Comparison with equations for partition into other solvents shows that, as regards partition of neutral (nonelectrolyte) compounds, NPOE would be a good model for 1,2-dichloroethane and for nitrobenzene. In terms of partition of ions and ionic species, NPOE is quite similar to 1,2-dichloroethane and not far away from other aprotic solvents such as nitrobenzene.
    • Paternal smoking as a cause for transgenerational damage in the offspring

      Anderson, Diana; Schmid, Thomas E.; Baumgartner, Adolf (2015)
      In 2013, the World Health Organization referred to tobacco smoking as an epidemic and a great threat to human health. Despite the obvious exposures from first- and secondhand smoking contributing to illnesses, an increased cancer risk, and death, there is a hidden risk to the next generation(s) from transgenerational mutations. In human populations, paternal preconceptional germ cell damage leading to genomic instability in offspring has always been difficult to evaluate as preconceptional and gestational exposures usually cannot be analyzed independently. Clear indications have been found that the effect of pre- and periconceptional paternal smoking may have been transmitted to the offspring via the spermatozoal genome and epigenome. Hence, cigarette smoke has to be considered a human germ cell mutagen due to its potential of inducing transgenerational DNA alterations in the unexposed F1 offspring of smoking-exposed fathers. For cohort studies, the practice of almost exclusively employing mother–childbirth pairs for the evaluation of lifestyle factors, such as smoking, while excluding the fathers’ contribution has to be reconsidered. Evidence now strongly points to the necessity of including the fathers in order not to miss paternal transgenerational damage in the offspring. This applies for genetic, epigenetic, and other transmissible effects.
    • Pathobiology of chemotherapy-induced hair loss.

      Paus, R.; Haslam, I.S.; Sharov, A.A.; Botchkarev, Vladimir A. (2013)
      Hair loss can be a psychologically devastating adverse effect of chemotherapy, but satisfactory management strategies for chemotherapy-induced alopecia remain elusive. In this Review we focus on the complex pathobiology of this side-effect. We discuss the clinical features and current management approaches, then draw upon evidence from mouse models and human hair-follicle organ-culture studies to explore the main pathobiology principles and explain why chemotherapy-induced alopecia is so challenging to manage. P53-dependent apoptosis of hair-matrix keratinocytes and chemotherapy-induced hair-cycle abnormalities, driven by the dystrophic anagen or dystrophic catagen pathway, play important parts in the degree of hair-follicle damage, alopecia phenotype, and hair-regrowth pattern. Additionally, the degree of hair-follicle stem-cell damage determines whether chemotherapy-induced alopecia is reversible. We highlight the need for carefully designed preclinical research models to generate novel, clinically relevant pointers to how this condition may be overcome.
    • Pathogens

      Lazenby, J.; Chang, Chien-Yi (2014)