2,882 research outputs found
Building robustness research during World War II
No full textThis study reviews research carried out in the U.K. to understand and improve the robustness of buildings when subject to blast from high explosive bombs. The work concentrates on the performance of ordinary civilian buildings, with particular emphasis on multi-storey buildings framed in either reinforced concrete or structural steelwork. At the time, some of the data was used to enhance conventional building construction, principally on Government buildings, and some was used to aide post-war hardened building construction. The two main UK researchers whose work is the basis of this paper (Professor Sir Dermot Christopherson and Professor Lord Baker) identified a number of building weaknesses that led to local or progressive collapse, including connections in steel framed buildings, as well as detailing weaknesses in reinforced concrete constructions. This paper reviews these features, as well as those that added resilience to bomb damage, with particular emphasis to the use of masonry infill panels in framed buildings. Much of the information on building performance is relevant to today's engineers engaged in the design of buildings to survive blast from terrorist attacks involving the vehicle borne improvised explosive device
In silico modelling--pharmacophores and hERG channel models
No full textIn computational drug design, modelling studies are undertaken following two main strategies that depend on which information is available. If experimental data exist only for the molecules displaying the biological property of interest, a so-called ligand-based approach is taken; if information is available on the macromolecular target(s) of the compounds (e.g. proteins' 3D structures), target-based studies can be carried out. Recently, in the field of hERG K+-channel blocking drugs, pharmacophoric (ligand-based) studies started appearing aimed at determining the physicochemical features associated with the channel block, and also at predicting the hERG blocking potential of compounds. However, partial homology models (target-based) of the hERG channel have also been built and used as working tools to interpret electrophysiological and mutagenesis studies. Here, we review some of the ligand- and target-based in silico studies carried out on hERG, focusing on both their main characteristics and their meaning. In addition, we discuss some methodological aspects of the computational work that in our opinion should be considered, in view of the construction of reliable models possibly able to predict the functional behaviour of the channel system and the blocking potential of drugs
Pathophysiological roles of P2 receptors in glial cells
No full textExtracellular nucleotides act through specific receptors on target cells: the seven ionotropic P2X and the eight G protein-coupled P2Y receptors. All these receptors are expressed by brain astroglia and microglia. In astrocytes, P2 receptors have been implicated in short-term calcium-dependent cell–cell communication. Upon mechanical stimulation or activation by other transmitters, astrocytes release ATP and respond to ATP with a propagating wave of intracellular calcium increases, allowing a homotypic astrocyte–astrocyte communication, as well as an heterotypic signalling which also involves neurons, oligodendrocytes and microglia. Astrocytic P2 receptors also mediate reactive astrogliosis, a reaction contributing to neuronal death in neurodegenerative diseases. Signalling leading to inflammatory astrogliosis involves induction of cyclo-oxygenase 2 through stimulation of ERK1,2 and of the transcriptional factors AP-1 and NF-κB. Microglia also express several P2 receptors linked to intracellular calcium increases. P2 receptor subtypes are differentially regulated by typical proinflammatory signals for these cells (e.g. lipopolysaccharide), suggesting specific roles in brain immune responses. Globally, these findings highlight the roles of P2 receptors in glial cell pathophysiology suggesting a contribution to neurodegenerative diseases characterized by excessive gliosis and neuro-inflammation. They also open up the possibility of modulating brain damage by ligands selectively targeting the specific P2 receptor subtypes involved in the gliotic response
Rapporteur’s report – innovative geotechnologies for energy transition
No full textThe 9th Society for Underwater Technology (SUT) International Conference on Offshore Site Investigation and Geotechnics (OSIG) closed with a Rapporteur’s report given by the author. This paper provides a record of that report, transcribed from a video recording. The presentation slides are shown as Figures.</p
DEFRApH - Sample collection and handling procedures
No full textAll chemical and biogeochemical process in the sea are affected by the acidity of the water. Acidity is therefore fundamental property of seawater. The growing concern that the acidity of the oceans might be increasing has revealed weaknesses in our knowledge of this fundamental property and its variation in space and time. In 2008 the DEFRApH project (DEFRA contract ME4133) was initiated to provide this missing information in UK related waters. It required sampling for and analysis of the total inorganic carbon and total alkalinity content of samples. This reports documents the procedures sued for sampling. A companion document Hartman Dumousseaud and Roberts (NOC Internal Document No. 01) describes in detail the analytical procedures used and the calculation of the results
Growth factor gradients in vascular patterning
No full textGrowth factor gradients regulate many developmental processes. VEGF-A is distributed in a graded fashion in growing tissues in order to direct sprouting of new vessels. Growth factor gradients can be formed by regulated production, retention, controlled release and degradation. VEGF-A production is controlled by hypoxia while its retention depends on the C-terminal heparin-binding motifs present in the longer splice-isoforms, VEGF164 and 188. This motif confers binding to the cell surface and the surrounding extracelluar matrix. The short isoform VEGF120 is diffusible and hence fails to direct endothelial tip cell migration. Conditional inactivation of heparan sulfate proteoglycans in the cells that produce VEGF results similarly in misguidance of the tip cells. Studying retinal developmental angiogenesis and pathological neovascularization side-by-side in the mouse retina, we find that endothelial tip cell guidance and stalk cell proliferation control are disrupted in neovascularization due to a loss of VEGF-A retention. The cause for this is proteolytic cleavage of VEGF-A by matrix metalloproteases (MMP) derived mostly from macrophages infiltrating the ischaemic retinal areas. Genetic or pharmacological inhibition of macrophage infiltration or MMP activity can rescue guided revascularization at the expense of pre-retinal neovascularization. Disruption of VEGF-A gradients provides a novel concept for the mechanism underlying pathological patterning in ocular disease
The role of inflammation for tumour growth and tumour suppression
No full textThe relationship between inflammation and tumour growth is poorly understood. The quality, quantity and time point of the inflammatory response may decide whether inflammation supports or inhibits tumour growth. Three examples are given that illustrate the different role of inflammation for tumour growth. It will be shown that tumour infiltrating macrophages can contribute to tumour rejection, can be essential for tumour growth or can occur as innocent bystander cells in tumours. Then it will be shown that the timely arrival of T cells at the tumour site is critical for tumour rejection and that non-bone marrow-derived tumour stromal cells are important targets during tumour rejection. Finally, a protective inflammatory response against the chemical carcinogen methylcholanthrene (MCA) will be discussed. This response is related to a tissue repair response induced by the tissue damaging effects of the carcinogen in the course of which MCA is encapsulated and no longer able to induce tumours
Elastic fibre assembly: Macromolecular interactions
No full textTo investigate the mechanisms behind elastic fibre assembly, we studied the molecular interactions between elastin and microfibrillar components using solid-phase binding assays. Fibrillin 1, purified from tissue using reductive-saline extraction, showed no binding to microfibril-associated glycoprotein (MAGP) or tropoelastin. MAGP, however, was found to bind specifically to tropoelastin in a divalent-cation independent manner. Antibody inhibition studies indicated that the C-terminus of tropoelastin defined the interactive site with MAGP. MAGP and fibrillin were also substrates for transglutaminase, which may provide an important mechanism for stabilizing microfibrillar structure. In other studies we found that a major cross-linking region in elastin is formed through the association of domains encoded by exons 10, 19 and 25 of tropoelastin and that the three chains are joined together by one desmosine and two lysinonorleucine cross-links
Author Correction:Prefrontal cortical ChAT-VIP interneurons provide local excitation by cholinergic synaptic transmission and control attention (Nature Communications, (2019), 10, 1, (5280), 10.1038/s41467-019-13244-9)
No full textThe original version of this Article contained an error in the spelling of the author Wilma D.J. van de Berg, which was incorrectly given as Wilma D.J. van den Berg. This has now been corrected in both the PDF and HTML versions of the Article.</p
Sunitinib treatment exacerbates intratumoral heterogeneity in metastatic renal cancer
No full textThis work was supported by the Chief Scientist Office, Scotland (ETM37; to G.D. Stewart, A.C.P. Riddick, M. Aitchison, and D.J. Harrison), Cancer Research UK (Experimental Cancer Medicine Centre; to T. Powles, London and D.J. Harrison, Edinburgh), Medical Research Council (to A. Laird and D.J. Harrison), Royal College of Surgeons of Edinburgh (to A. Laird), Melville Trust (to A. Laird), Medical Research Council (MC_UU_12018/25; to I.M. Overton), Royal Society of Edinburgh Scottish Government Fellowship cofunded by Marie Curie Actions (to I.M. Overton), Renal Cancer Research Fund (to G.D. Stewart), Kidney Cancer Scotland (to G.D. Stewart) and an educational grant from Pfizer (to T. Powles).Purpose: The aim of this study was to investigate the effect of VEGF targeted therapy (sunitinib) on molecular intratumoral heterogeneity (ITH) in metastatic clear cell renal cancer (mccRCC). Experimental design: Multiple tumor samples (n=187 samples) were taken from the primary renal tumors of mccRCC patients who were sunitinib treated (n=23, SuMR clinical trial) or untreated (n=23, SCOTRRCC study). ITH of pathological grade, DNA (aCGH), mRNA (Illumina Beadarray) and candidate proteins (reverse phase protein array) were evaluated using unsupervised and supervised analyses (driver mutations, hypoxia and stromal related genes). ITH was analysed using intratumoral protein variance distributions and distribution of individual patient aCGH and gene expression clustering. Results: Tumor grade heterogeneity was greater in treated compared to untreated tumors (P=0.002). In unsupervised analysis, sunitinib therapy was not associated with increased ITH in DNA or mRNA. However, there was an increase in ITH for the driver mutation gene signature (DNA and mRNA) as well as increasing variability of protein expression with treatment (p<0.05). Despite this variability, significant chromosomal and transcript changes to key targets of sunitinib, such as VHL, PBRM1 and CAIX, occurred in the treated samples. Conclusions: These findings suggest that sunitinib treatment has significant effects on the expression and ITH of key tumor and treatment specific genes/proteins in mccRCC. The results, based on primary tumor analysis, do not support the hypothesis that resistant clones are selected and predominate following targeted therapy.Peer reviewe
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