2,779 research outputs found
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
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
Pharmacological characterization of the bifunctional opioid ligand H-Dmt-Tic-Gly-NH-Bzl (UFP-505)
No full textBACKGROUND: While producing good-quality analgesia, μ-opioid (MOP) receptor activation produces a number of side-effects including tolerance. Simultaneous blockade of δ-opioid (DOP) receptors has been shown to reduce tolerance to morphine. Here, we characterize a prototype bifunctional opioid H-Dmt-Tic-Gly-NH-Bzl (UFP-505).
METHODS: We measured receptor binding affinity in Chinese hamster ovary (CHO) cells expressing recombinant human MOP, DOP, k-opioid (KOP), nociceptin/orphanin (NOP) receptors. For activation, we measured the binding of GTPγ(35)S to membranes from CHO(hMOP), CHO(hDOP), rat cerebrocortex, and rat spinal cord. In addition, we assessed 'end organ' responses in the guinea pig ileum and mouse vas deferens.
RESULTS: UFP-505 bound to CHO(hMOP) and CHO(hDOP) with (binding affinity) pK(i) values of 7.79 and 9.82, respectively. There was a weak interaction at KOP and NOP (pK(i) 6.29 and 5.86). At CHO(hMOP), UFP-505 stimulated GTPγ(35)S binding with potency (pEC(50)) of 6.37 and in CHO(hDOP) reversed the effects of a DOP agonist with affinity (pK(b)) of 9.81 (in agreement with pK(i) at DOP). UFP-505 also stimulated GTPγ(35)S binding in rat cerebrocortex and spinal cord with pEC(50) values of 6.11-6.53. In the guinea pig ileum (MOP-rich preparation), UFP-505 inhibited contractility with pEC(50) of 7.50 and in the vas deferens (DOP-rich preparation) reversed the effects of a DOP agonist with an affinity (pA(2)) of 9.15.
CONCLUSIONS: We have shown in a range of preparations and assays that UFP-505 behaves as a potent MOP agonist and DOP antagonist; a MOP/DOP bifunctional opioid. Further studies in dual expression systems and whole animals with this prototype are warranted
Recent advances in the non-pharmacological management of postoperative nausea and vomiting
No full textSunitinib 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
Reply to the discussion by McCarron on “Modelling spatial variability in as-laid embedment for high pressure and high temperature (HPHT) pipeline design”
No full textN/AThe accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author
Pharmacological profile of the cyclic nociceptin/orphanin FQ analogues c[Cys(10,14)]N/OFQ(1-14)NH2 and c[Nphe(1),Cys(10,14)]N/OFQ(1-14)NH2
No full textIn this study we describe the activity of two
cyclic nociceptin/orphanin FQ (N/OFQ) peptides; c[Cys10,14]N/
OFQ(1–14)NH2 (c[Cys10,14]) and its [Nphe1] derivative
c[Nphe1,Cys10,14]N/OFQ(1–14)NH2 (c[Nphe1,Cys10,14]) in
native rat and mouse and recombinant human N/OFQ receptors
(NOP). Cyclisation may protect the peptide from
metabolic degradation.
In competition binding studies of rat, mouse and human
NOP the following rank order pKi was obtained: N/OFQ(1–
13)NH2(reference agonist)>N/OFQ=c[Cys10,14]>>c[Nphe1Cys10,14].
In GTPγ35S studies of Chinese hamster ovary cells expressing
human NOP (CHOhNOP) c[Cys10,14] (pEC50 8.29)
and N/OFQ(1–13)NH2 (pEC50 8.57) were full agonists
whilst c[Nphe1Cys10,14] alone was inactive. Following 30 min
pre-incubation c[Nphe1Cys10,14] competitively antagonised
the effects of N/OFQ(1–13)NH2 with a pA2 and slope factor
of 6.92 and 1.01 respectively. In cAMP assays c[Cys10,14]
(pEC50 9.29, Emax 102% inhibition of the forskolin stimulated
response), N/OFQ(1–13)NH2 (pEC50 10.16, Emax
103% inhibition) and c[Nphe1Cys10,14] (~80% inhibition
at 10 μM) displayed agonist activity. In the mouse vas
deferens c[Cys10,14] (pEC50 6.82, Emax 89% inhibition of
electrically evoked contractions) and N/OFQ(1–13)NH2
(pEC50 7.47, Emax 93% inhibition) were full agonists whilst
c[Nphe1Cys10,14] alone was inactive. c[Nphe1Cys10,14]
(10 μM) competitively antagonised the effects of N/OFQ(1–
13)NH2 with a pKB of 5.66. In a crude attempt to assess
metabolic stability, c[Cys10,14] was incubated with rat brain
membranes and then the supernatant assayed for remaining
peptide. Following 60 min incubation 64% of the 1 nM
added peptide was metabolised (compared with 54% for
N/OFQ-NH2).
In summary, we report that c[Cys10,14] is a full agonist
with a small reduction in potency but no improvement in
stability whilst c[Nphe1Cys10,14] displays tissue (antagonist
in the vas deferens) and assay (antagonist in the GTPγ35S
assay and agonist in cAMP assay) dependent activity
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