15 research outputs found
Glucagon-like peptide-1-(9-36) amide is a major metabolite of glucagon-like peptide-1-(7-36) amide after in vivo administration to dogs, and it acts as an antagonist on the pancreatic receptor
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Old Maps Online - Final Article (report)
No full textOld Maps Online is an online search tool for historical maps. It uniquely draws together map collections from libraries around the world into a single, easy to use search interface. Using cutting edge technology the user searches for old maps by location, narrowed by date, rather than through more traditional catalogue listings.
Following a successful early launch in February 2012 its popularity has grown continuously. We have delivered large benefits to end users, but this project, and the two conferences it organized, have also succeeded in raising awareness of the importance of spatial metadata for historical maps within the libraries world.
The project aimed to create a single search interface allowing users to find old maps in multiple library collections around the world without having to know either which library held the map or any of the conventional catalogue information such as title, author or publisher, which have traditionally been used when searching for maps. Instead users search using geography, either by typing in a place name or by utilizing the interactive map view, to find maps showing the place they are interested in. They receive instant results as thumbnails with accompanying metadata which each provide a direct link to a full size interactive scan of that map on the website of the host institution.
During the project there has been a steady stream of interest from map librarians wishing to become involved. We launched with just five collections but by February 2013 we provided access to nineteen, and were working to resolve metadata issues from several more.
As well as creating the Old Maps Online search interface, we aimed to raise awareness of the usefulness of firstly adding spatial metadata to conventional library metadata; and secondly of the need for stable and consciously designed URIs (Uniform Resource Identifiers) rather than URLs as web addresses. Using URIs raises citation rates, increases the readability of the address for humans, and grants longevity to web addresses by removing dependencies on both server software and organizational structures
Author Correction: Molecular engineering of safe and efficacious oral basal insulin
No full textAn amendment to this paper has been published and can be accessed via a link at the top of the paper
Vladimir Burtsev and the Russian revolutionary emigration: surveillance of foreign political refugees in London, 1891-1905.
No full textPhDThe thesis describes the early life in emigration of the Russian revolutionary, historian
and radical journalist Vladimir L'vovich Burtsev (17/29 November 1862 - 21 August
1942). Particular emphasis is placed on the nature and extent of the police
surveillance of Burtsev and the émigré community in Europe during the period. The
relationship between the Criminal Investigation Department of London's
Metropolitan Police and their Russian counterparts in Europe - the Zagranichnaia
agentura, ('Foreign Agency') - is examined in detail.
Burtsev's biography has great contemporary relevance, unfolding, as it does, in an
atmosphere of increasing anxiety in Britain (both governmental and non-official)
about growing numbers of foreign anarchists, terrorists, and `aliens' in general (which
would lead, in due course, to the passing of the 1905 Aliens Act) and the increasingly
interventionist police methods of the era. The thesis describes Burtsev's relationship
with the émigré community and its British supporters, examines his (at times extreme)
political views and reviews the radical journalism which led to his trial and
imprisonment in 1898. This, the `Burtsev affair', signalled a major shift in British
government policy towards political refugees on the one hand and to international
counter-terrorist co-operation on the other and it is one of the aims of this thesis to
detail the reasons for these changes
Adipocyte differentiation of 3T3-L1 preadipocytes is dependent on lipoxygenase activity during the initial stages of the differentiation process.
No full textInternational audienceAdipocytes play a central role in whole-body energy homoeostasis. Complex regulatory transcriptional networks control adipogensis, with ligand-dependent activation of PPARgamma (peroxisome proliferator-activated receptor gamma) being a decisive factor. Yet the identity of endogenous ligands promoting adipocyte differentiation has not been established. Here we present a critical evaluation of the role of LOXs (lipoxygenases) during adipocyte differentiation of 3T3-L1 cells. We show that adipocyte differentiation of 3T3-L1 preadipocytes is inhibited by the general LOX inhibitor NDGA (nordihydroguaiaretic acid) and the 12/15-LOX selective inhibitor baicalein. Baicalein-mediated inhibition of adipocyte differentiation was rescued by administration of rosiglitazone. Treatment with baicalein during the first 4 days of the differentiation process prevented adipocyte differentiation; supplementation with rosiglitazone during the same period was sufficient to rescue adipogenesis. Accordingly, we demonstrate that adipogenic conversion of 3T3-L1 cells requires PPARgamma ligands only during the first 4 days of the differentiation process. We show that the baicalein-sensitive synthesis of endogenous PPARgamma ligand(s) increases rapidly upon induction of differentiation and reaches a maximum on days 3-4 of the adipocyte differentiation programme. The conventional platelet- and leucocyte-type 12(S)-LOXs and the novel eLOX-3 (epidermis-type LOX-3) are expressed in white and brown adipose tissue, whereas only eLOX-3 is clearly expressed in 3T3-L1 cells. We suggest that endogenous PPARgamma ligand(s) promoting adipocyte differentiation are generated via a baicalein-sensitive pathway involving the novel eLOX-3
Synthesis and Biological and Structural Characterization of the Dual-Acting Peroxisome Proliferator-Activated Receptor α/γ Agonist Ragaglitazar
No full textA new and improved synthesis of the peroxisome proliferator-activated receptor (PPAR) agonist
ragaglitazar applicable for large-scale preparation has been developed. The convergent synthetic
procedure was based on a novel enzymatic kinetic resolution step. The conformation of
ragaglitazar bound to the hPPARγ receptor was quite different compared to the single-crystal
structures of the l-arginine salt of ragaglitazar. In particular, the phenoxazine ring system
had varying orientations. Ragaglitazar had high affinity for the hPPARα and -γ receptors with
IC50 values of 0.98 and 0.092 μM, respectively. The lack of hPPARδ activity could be explained
by the absence of binding in the tail-up pocket in the hPPARδ receptor, in contrast to the
hPPARδ agonist GW2433, which was able to bind in both the tail-up and tail-down pockets of
the receptor
Human Glucagon Receptor Antagonists with Thiazole Cores. A Novel Series with Superior Pharmacokinetic Properties
No full textThe aim of the work presented here was to design and synthesize potent human glucagon receptor antagonists with improved pharmacokinetic (PK) properties for development of pharmaceuticals for the treatment of type 2 diabetes. We describe the preparation of compounds with cyclic cores (5-aminothiazoles), their binding affinities for the human glucagon and GIP receptors, as well as affinities for rat, mouse, pig, dog, and monkey glucagon receptors. Generally, the compounds had slightly less glucagon receptor affinity compared to compounds of the previous series, but this was compensated for by much improved PK profiles in both rats and dogs with high oral bioavailabilities and sustained high plasma exposures. The compounds generally showed species selectivity for glucagon receptor binding with poor affinities for the rat, mouse, rabbit, and pig receptors. However, dog and monkey glucagon receptor affinities seem to reflect the human situation. One compound of this series, 18, was tested intravenously in an anesthetized glucagon-challenged monkey model of hyperglucagonaemia and hyperglycaemia and was shown dose-dependently to decrease glycaemia. Further, high plasma exposures and a long plasma half-life (5.2 h) were obtained
6-Chloro-3-alkylamino-4<i>H</i>-thieno[3,2<i>-e</i>]-1,2,4-thiadiazine 1,1-Dioxide Derivatives Potently and Selectively Activate ATP Sensitive Potassium Channels of Pancreatic β-Cells
No full text6-Chloro-3-alkylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide derivatives were synthesized and characterized as activators of adenosine 5‘-triphosphate (ATP) sensitive potassium
(KATP) channels in the β-cells by measuring effects on membrane potential and insulin release
in vitro. The effects on vascular tissue in vitro were measured on rat aorta and small mesenteric
vessels. Selected compounds were characterized as competitive inhibitors of [3H]glibenclamide
binding to membranes of HEK293 cells expressing human SUR1/Kir6.2 and as potent inhibitors
of insulin release in isolated rat islets. 6-Chloro-3-(1-methylcyclobutyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (54) was found to bind and activate the SUR1/Kir6.2 KATP
channels in the low nanomolar range and to be at least 1000 times more potent than the
reference compound diazoxide with respect to inhibition of insulin release from rat islets. Several
compounds, e.g., 3-propylamino- (30), 3-isopropylamino- (34), 3-(S)-sec-butylamino- (37), and
3-(1-methylcyclopropyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (53), which were
found to be potent and β-cell selective activators of KATP channels in vitro, were found to inhibit
insulin secretion in rats with minimal effects on blood pressure and to exhibit good oral
pharmacokinetic properties
Molecular Engineering of Insulin Icodec, the First Acylated Insulin Analog for Once-Weekly Administration in Humans
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