1,256 research outputs found
NeSI Futures
No full textNeSI is a key feature of the New Zealand investment in science infrastructure. It was first
established in mid-2011 and is now in its 8th year of operations. Currently NeSI is formulating its
long-term strategic plan having completed a successful external evaluation in mid-2016. Over the
last year NeSI has carried out a range of activities to inform its strategic plans, including a research
consultation, an international benchmark study, a survey of its migration to its new infrastructure,
and a review of its training activities. Looking ahead at the key challenges faced by the research
sector, this session outlines what NeSI has learnt at a high-level, and map out the journey ahead. ABOUT THE AUTHOR(S) Nick Jones is NeSI’s founding Director, having established and led NeSI alongside a team of
colleagues and peers since inception in mid-2011. Nick is responsible for NeSI’s strategic
directions and performance overall, bringing together a talented and diverse array of people, and
their institutions and interests. Nick has over 20 years’ experience in innovating in advanced
information/computing technology in sectors including education, science and research. Nick
established the eResearch NZ conference series in 2010 to support the sector coming together in
the spirit of community to share experiences and explore directions in an area so critical to our
future prosperity as a nation.</div
Potent muscarinic antagonists bearing 1,4-dioxane scaffold
No full textMuscarinic receptor antagonists are used in the treatment of airway, bladder, and gastrointestinal smooth muscle disorders. In the treatment of overactive bladder (OAB) and OAB symptoms they are often associated with detrusor overactivity (DO) and exert their effects by inhibiting the binding of acetylcholine at muscarinic receptors M2 and M3 on detrusor smooth muscle cells and other structures within the bladder wall.1
(1,3-dioxolan-4-yl)-N,N,N-trimethylmethanaminium iodide nucleus has been used for many years as a scaffold for its ability to give potent muscarinic agonists or antagonists, depending on the size of the substituent in position 2 (methyl or bulkier group, respectively).2 The enlargement of the 1,3-dioxolane nucleus of 1 by inserting a methylene group between the 1-oxygen atom and the 2-carbon atom afforded the potent muscarinic agonist 2, which preferentially activated M2 and M3 subtypes.3 Therefore, to obtain a potent antagonist useful in the treatment of OAB, in the present study two phenyl rings have been inserted in position 6 of the 1,4-dioxane scaffold (compound 3). Moreover, since it is well known that muscarinic receptors display stereoselective requirements and the biological activity of muscarinic ligands is closely related to their stereochemistry,4 the racemate 3 has also been resolved into its two enantiomers via an oxazolidinone auxiliary mediated resolution. The absolute configuration of the two enantiomers has been determined through X-ray diffraction analysis of the dextrorotatory form.
The pharmacological profile of racemate 3 and its two enantiomers was evaluated by receptor binding assays on Chinese hamster ovary (CHO) cells, expressing the five human muscarinic subtypes (hm1-hm5). From preliminary results compound 3 showed nM affinity values significantly similar to those of N-methylscopolamine at all muscarinic subtypes. The eutomer was the levorotatory form (S)-(−)-3 at all muscarinic M1-M5 subtypes, with eudismic ratios of 32, 12, 42, 102 and 63, respectively.
References
1) Abrams, P.; Andersson, K.-E. BJU Int. 2007,100, 987-1006
2) a) Angeli, P. Farmaco 1995, 50, 565-77. b) Angeli, P. Farmaco 1998, 53, 1-21.
3) Piergentili, A.; Quaglia, W.; Giannella, M.; Del Bello, F.; Buccioni, M.; Nesi, M.; Matucci, R. Bioorg. Med. Chem. Lett. 2008, 18, 614-618.
4) Scapecchi, S.; Matucci, R.; Bellucci, C.; Buccioni, M.; Dei, S.; Guandalini, L.; Martelli, C.; Manetti, D.; Martini, E.; Marucci, G.; Nesi, M.; Romanelli, M. N.; Teodori, E.; Gualtieri, F. J. Med. Chem. 2006, 49, 1925-1931
To break the embarrassment: Text comprehension skills and figurative competence in skilled and less-skilled text comprehenders
No full textThe aim of the present study was to investigate children's ability to complete idiom fragments embedded in stories. Previous studies found that children's and preadolescents' ability to comprehend a text was related to their ability to understand an idiomatic expression (Cain, Oakhill, & Lemmon, 2005; Levorato, Nesi, & Cacciari, 2004; Nippold, Moran, & Schwarz, 2001). Comprehension and production processes share a vast amount of conceptual and lexical knowledge. Hence, we hypothesized that children's text reading comprehension skills also might be related to their ability to produce nonliteral completions. Skilled and less-skilled text comprehenders (age range from 7.4 to 10.3) were presented with short stories that ended with an idiomatic fragment (e.g., Paul broke the... for the idiom break the ice) and-were asked to complete the story. The children's completions were coded as Literal, Idiomatic, or Figurative as in previous studies (Levorato & Cacciari, 1992, 1995). The results showed that children's ability to understand a text was related to their ability to complete idiomatic fragments figuratively. Less-skilled comprehenders provided more literal completions than skilled comprehenders who, in turn, provided more idiomatic completions
Megaloglossus azagnyi Nesi et al. 2012
No full textMegaloglossus azagnyi Nesi et al., 2012 This species was not previously recorded from Mt Nimba. This species was only captured within old growth or secondary forest at relatively low altitudes on both Liberian and Guinean sides of the mountain between 450 m and 690 m a.s.l. We follow Nesi et al. (2013) in recognising this newly described West African taxon as a species separate from M. woermanni, which occurs further east.Published as part of Monadjem, Ara, Richards, Leigh & Denys, Christiane, 2016, An African bat hotspot: the exceptional importance of Mount Nimba for bat diversity, pp. 359-375 in Acta Chiropterologica 18 (2) on page 364, DOI: 10.3161/15081109ACC2016.18.2.005, http://zenodo.org/record/394248
How NeSI helps Manaaki Whenua -Landcare Research monitor land cover changes
No full textWe describe a NeSI consultancy project, which, during November 2018, helped Manaaki
Whenua - Landcare Research (MWLR) increase its capacity to analyse large numbers of satellite
images.ABOUT THE AUTHOR(S)Alex Pletzer is a Research Software Engineer working for NeSI and physically located at
NIWA. When he’s not helping researchers squeeze performance out of their code, you
might find him windsurfing around Wellington or walking with his wife on top of a hill.
-James Shepherd is Researcher for Manaaki Whenua – Landcare Research at Palmerston
NorthMandes Schönherr is Application Support Specialist for NeSI at NIWA, Wellington Chris Scott is Scientific Programmer for NeSI at the University of Auckland</div
Gamma-convergence of power-law functionals, variational principles in L-infinity, and application
No full textTwo Gamma-convergence results for a general class of power-law functionals are obtained in the setting of A-quasiconvexity. New variational principles in L^{infty} are introduced, allowing for the description of the yield set in the context of a simplified model of polycrystal plasticity. A number of highly degenerate nonlinear partial differential equations arise as Aronsson equations associated with these variational principles
Copresence of 1,4-dioxane and quinuclidine nuclei in the design of novel muscarinic antagonists
No full textThe five muscarinic receptors are involved in many physiological functions and, therefore, the potential therapeutical applications of muscarinic agonists and antagonists are numerous. However, the high homology of the orthosteric binding sites of the different subtypes (amino acid sequence identity > 60%) makes particularly difficult the achievement of selective ligands (1). Candidates which are more likely to discriminate among subtypes are obviously antagonists because of their ability to interact with sites in the extracellular loops or with accessory residues of the receptor. In the search for novel muscarinic antagonists we opted for molecules bearing the 1,4-dioxane nucleus, which has proved to be a suitable scaffold for targeting muscarinic receptors (2). Such a scaffold, substituted in position 6 with two phenyl rings, has been linked by an oxymethylene bridge to a quinuclidine nucleus, which is present in numerous muscarinic agents as well. The presence of this nucleus has the advantage of including in the final compound a second stereogenic center, thus achieving a more selective effect, after the separation of the four enantiomers. The synthesis of the novel compounds, the characterization of their structure, and the preliminary pharmacological results will be discussed.
References:
1) Eglen, R. M. Muscarinic receptor subtype pharmacology and physiology. Prog. Med. Chem. 2005, 43, 105-136.
2) Piergentili A.; Quaglia, W.; Del Bello, F.; Giannella, M.; Pigini, M.; Barocelli, E.; Bretoni, S.; Matucci, R.; Nesi, M.; Bruni, B.; Di Vaira, M. Properly substituted 1,4-dioxane nucleus favours the selective M3 muscarinic receptor activation. Bioorg. Med. Chem. 2009, 17, 8174-8185 and references therein
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