Helping You Find Full Text Journal Articles

Search Results:

Author: David House (31)


Jan
2018

The MKK1/2 kinase tumour progression locus 2 (TPL-2) is critical for the production of tumour necrosis factor alpha (TNFα) in innate immune responses and a potential anti-inflammatory drug target. Several earlier pharmaceutical company screens with the isolated TPL-2 kinase domain have identified small-molecule inhibitors that specifically block TPL-2 signalling in cells, but none of these have progressed to clinical development. We have previously shown that TPL-2 catalytic activity regulates TNF production by macrophages while associated with NF-κB1 p105 and ABIN-2, independently of MKK1/2 phosphorylation via an unknown downstream substrate.

View Full Text PDF Listings View primary source full text article PDFs.

Oct
2017

More than half of all pharmaceuticals are chiral compounds. Although the enantiomers of chiral compounds have the same chemical structure, they can exhibit marked differences in physiological activity; therefore, it is important to remove the undesirable enantiomer. Chromatographic separation of chiral enantiomers is one of the best available methods to get enantio-pure substances, but the optimization of the experimental conditions can be very time-consuming.

View Full Text PDF Listings View primary source full text article PDFs.

Oct
2016

Acute respiratory distress syndrome is refractory to pharmacological intervention. Inappropriate activation of alveolar neutrophils is believed to underpin this disease's complex pathophysiology, yet these cells have been little studied.
To examine the functional and transcriptional profiles of patient blood and alveolar neutrophils compared with healthy volunteer cells, and to define their sensitivity to phosphoinositide 3-kinase inhibition.

View Full Text PDF Listings View primary source full text article PDFs.

Feb
2015

Acute respiratory distress syndrome (ARDS) is characterised by diffuse neutrophil-mediated alveolar inflammation. Recently, we demonstrated that blood polymorphonuclear leucocytes (PMNs) in ARDS are basally activated, and exhibit aberrant oxidative burst and survival responses. The molecular mechanisms governing ARDS PMN function and longevity are incompletely understood.

View Full Text PDF Listings View primary source full text article PDFs.

Jun
2015

This investigation explores perceptual and acoustic characteristics of children's successful and unsuccessful productions of /t/ and /k/, with a specific aim of exploring perceptual sensitivity to phonetic detail, and the extent to which this sensitivity is reflected in the acoustic domain. Recordings were collected from 4- to 8-year-old children with a speech sound disorder (SSD) who misarticulated one of the target plosives, and compared to productions recorded from peers with typical speech development (TD). Perceptual responses were registered with regards to a visual-analog scale, ranging from "clear [t]" to "clear [k].

View Full Text PDF Listings View primary source full text article PDFs.

Jan
2015

Controlling the properties of lead molecules is critical in drug discovery, but sourcing large numbers of lead-like compounds for screening collections is a major challenge. A unified synthetic approach is described that enabled the synthesis of 52 diverse lead-like molecular scaffolds from a minimal set of 13 precursors. The divergent approach exploited a suite of robust, functional group-tolerant transformations.

View Full Text PDF Listings View primary source full text article PDFs.

Sep
2014

Rh-catalysed conjugate additions of 2-aminophenyl boronic acid derivatives were exploited in diastereoselective and asymmetric syntheses of tetrahydroquinolines. In both cases, combinatorial variation of the substitution of the tetrahydroquinoline ring system was possible.

View Full Text PDF Listings View primary source full text article PDFs.

Jun
2014

We explore children's perception of their own speech - in its online form, in its recorded form, and in synthetically modified forms. Children with phonological disorder (PD) and children with typical speech and language development (TD) performed tasks of evaluating accuracy of the different types of speech stimuli, either immediately after having produced the utterance or after a delay. In addition, they performed a task designed to assess their ability to detect synthetic modification.

View Full Text PDF Listings View primary source full text article PDFs.

Sep
2013

Drug-evoked synaptic plasticity in the mesolimbic system reshapes circuit function and drives drug-adaptive behavior. Much research has focused on excitatory transmission in the ventral tegmental area (VTA) and the nucleus accumbens (NAc). How drug-evoked synaptic plasticity of inhibitory transmission affects circuit adaptations remains unknown.

View Full Text PDF Listings View primary source full text article PDFs.

Feb
2014

There are increased numbers of pulmonary CD8 lymphocytes in COPD (chronic obstructive pulmonary disease). CRAC (calcium release-activation calcium) channels play a central role in lymphocyte activation though the regulation of the transcription factor NFAT (nuclear factor of activated T-cells). We studied the expression of NFAT in lungs from COPD patients compared with controls, and evaluated the effects of CRAC channel inhibition compared with corticosteroids on NFAT activation and cytokine production in CD8 cells from COPD patients.

View Full Text PDF Listings View primary source full text article PDFs.

Mar
2013

Loss of function mutations in the two key proteins which constitute Calcium-Release Activated Calcium (CRAC) channels demonstrate the critical role of this ion channel in immune cell function. The aim of this study was to demonstrate that inhibition of immune cell activation could be achieved with highly selective inhibitors of CRAC channels in vitro using cell preparations from human, rat, mouse and guinea-pig. Two selective small molecule blockers of CRAC channels; GSK-5498A and GSK-7975A were tested to demonstrate their ability to inhibit mediator release from mast cells, and pro-inflammatory cytokine release from T-cells in a variety of species.

View Full Text PDF Listings View primary source full text article PDFs.

Feb
2013

As the molecular composition of calcium-release activated calcium (CRAC) channels has been unknown for two decades, elucidation of selective inhibitors has been considerably hampered. By the identification of the two key components of CRAC channels, STIM1 and Orai1 have emerged as promising targets for CRAC blockers. The aim of this study was to thoroughly characterize the effects of two selective CRAC channel blockers on currents derived from STIM1/Orai heterologoulsy expressed in HEK293 cells.

View Full Text PDF Listings View primary source full text article PDFs.

Dec
1969

In this paper, we investigate how lexical tones interact with intonation, using data from the Austroasiatic language Kammu, one of few languages with two dialects whose only major phonological difference is the presence or absence of lexical tones. Northern (and Western) Kammu have developed tones in connection with the merger of voiceless and voiced initial consonants, while the non-tonal Eastern dialect kept the segmental opposition with no tones. We found the following prosodic hierarchy: (1) lexical tones, (2) phrase-final boundary tone, (3) focus marking.

View Full Text PDF Listings View primary source full text article PDFs.

Dec
2011

Sensory experience drives robust plasticity of sensory maps in cerebral cortex, but the role of inhibitory circuits in this process is not fully understood. We show that classical deprivation-induced whisker map plasticity in layer 2/3 (L2/3) of rat somatosensory (S1) cortex involves robust weakening of L4-L2/3 feedforward inhibition. This weakening was caused by reduced L4 excitation onto L2/3 fast-spiking (FS) interneurons, which mediate sensitive feedforward inhibition and was partially offset by strengthening of unitary FS to L2/3 pyramidal cell synapses.

View Full Text PDF Listings View primary source full text article PDFs.

Dec
1969

Research on the perception of faces has focused on the size, shape, and configuration of inherited features or the biological phenotype, and largely ignored the effects of adornment, or the extended phenotype. Research on the evolution of signaling has shown that animals frequently alter visual features, including color cues, to attract, intimidate or protect themselves from conspecifics. Humans engage in conscious manipulation of visual signals using cultural tools in real time rather than genetic changes over evolutionary time.

View Full Text PDF Listings View primary source full text article PDFs.

Jul
2011

The sequential use of Cu-catalyzed asymmetric allylic alkylation, olefin cross-metathesis, and Ir-catalyzed asymmetric allylic amination allows the concise, stereodivergent synthesis of complex chiral amines with complete regiocontrol and good diastereoselectivity, exemplified by the synthesis of a pair of diastereoisomeric unnatural branched amino acid derivatives.

View Full Text PDF Listings View primary source full text article PDFs.

Feb
2011

A novel series of indazole non-steroidal glucocorticoid receptor agonist has been discovered. This series features a sulfonamide central core and meta amides which interact with the extended ligand binding domain. This series has produced some of the most potent and least lipophilic agonists of which we are aware such as 20a (NFκB pIC(50) 8.

View Full Text PDF Listings View primary source full text article PDFs.

Jun
2010

Access to highly enantioenriched planar chiral [Cr(5-bromonaphthalene)(CO)(3)] (6), [Ru(eta(5)-C(5)R(5))(5-bromonaphthalene)][PF(6)] (42) and [Ru(eta(5)-C(5)R(5))(4-bromoindene)] (44) was sought using asymmetric hydrogenolysis of [Cr(5,8-dibromonaphthalene)(CO)(3)] (5), [Ru(eta(5)-C(5)R(5))(5,8-dibromonaphthalene)] (39) and [Ru(eta(5)-C(5)R(5))(4,7-dibromoindene)] (40), respectively. Initial efforts focused on the chromium complex 5. Pd(0) catalysts with dimethoxyethane as the solvent and LiBH(4) or NaBH(3)CN as a hydride source worked best.

View Full Text PDF Listings View primary source full text article PDFs.

View Full Text PDF Listings View primary source full text article PDFs.

Oct
2009

Crystallography and computer modeling have been used to exploit a previously unexplored channel in the glucocorticoid receptor (GR). Highly potent, nonsteroidal indazole amides showing excellent complementarity to the channel were designed with the assistance of the computational technique AlleGrow. The accuracy of the design process was demonstrated through crystallographic structural determination of the GR ligand-binding domain-agonist complex of the D-prolinamide derivative 11.

View Full Text PDF Listings View primary source full text article PDFs.

Aug
2009

Starting from a non-steroidal glucocorticoid agonist aryl pyrazole derivative, the NFkappaB agonist activity was optimised in an iterative process from pIC(50) 7.5 (for 7), to pIC(50) 10.1 (for 38E1).

View Full Text PDF Listings View primary source full text article PDFs.

Sep
2008

A direct convergent two-component synthesis of quinolines from alpha,beta-unsaturated ketones and o-aminophenylboronic acid derivatives is reported. The reaction is regiocomplementary to the traditional Skraup-Doebner-Von Miller synthesis and proceeds under basic rather than strongly acidic conditions. Quinolines substituted in the benzenoid ring can be accessed by using substituted o-aminophenylboronates prepared by direct palladium-catalyzed borylation of the corresponding o-bromoanilines.

View Full Text PDF Listings View primary source full text article PDFs.

Dec
2007

The synthesis and biological activity of tetrahydronaphthalene derivatives coupled to various heterocycles are described. These compounds are potent glucocorticoid receptor agonists with efficacy selectivity in an NFkappaB glucocorticoid receptor (GR) agonist assay (representing transrepression effects) over an MMTV GR agonist assay (representing transactivation effects). Quinolones, indoles, and C- and N-linked quinolines are some of the heterocycles that provide efficacy selectivity.

View Full Text PDF Listings View primary source full text article PDFs.

Aug
2007

The condensation of a 2-substituted-2-aminoethanol with methyl 2'-formylbiphenyl-2-carboxylate produces only two of the four possible axially chiral 6,7-dihydrodibenz[c,e]oxazolo[3,2-a]azepin-9(4bH)-ones (fused oxazolidine lactams), with kinetically controlled diastereoisomer ratios of up to 96 : 4. Within each lactam product the central chirality of the oxazolidine-fused benzylic position C(4b) is relayed to the biaryl axis with unit efficiency, the mis-matching of these stereogenic elements being prohibited due to strain, as predicted by molecular mechanics calculations. Diastereoisomeric lactam pairs can be equilibrated by heating with acid, and under these thermodynamic conditions reversed diastereoisomer ratios of up to 26 : 74 are observed.

View Full Text PDF Listings View primary source full text article PDFs.

Sep
2007

Starting from an established series of non-steroidal glucocorticoid receptor (GR) agonists, a large array was designed where a metabolically labile benzoxazinone moiety was replaced. Initial hits bound to GR but lacked agonist activity. Following two further iterations, potent GR agonists were discovered with 20D1E1 having NFkappaB agonism pIC(50) 8.

View Full Text PDF Listings View primary source full text article PDFs.

Jul
2006

The tetrahydronaphthalene-benzoxazine glucocorticoid receptor (GR) partial agonist 4b was optimized to produce potent full agonists of GR. Aromatic ring substitution of the tetrahydronaphthalene leads to weak GR antagonists. Discovery of an "agonist trigger" substituent on the saturated ring of the tetrahydronaphthalene leads to increased potency and efficacious GR agonism.

View Full Text PDF Listings View primary source full text article PDFs.

View Full Text PDF Listings View primary source full text article PDFs.

Nov
2003

The reductive aldol reaction of electron deficient aromatic compounds has been investigated and found to be a viable method for carbon-carbon bond formation. Reductions under ammonia and ammonia-free conditions were both capable of facilitating the aldol reaction although the latter showed more scope for reaction with enolisable aldehydes. Moreover, reduction under ammonia-free conditions allowed the addition of Lewis acids which improved stereoselectivity to favour the anti stereoisomer.

View Full Text PDF Listings View primary source full text article PDFs.

Jul
2003

Previous studies have shown that overexpression of the protein PSD-95 (postsynaptic density-95) selectively enhances AMPA receptor-mediated synaptic responses in hippocampal pyramidal cells. To determine whether this effect is related to synaptic plasticity at these synapses, we examined whether PSD-95 expression mimics long-term potentiation (LTP), and also whether it influences LTP and long-term depression (LTD) in hippocampal slice cultures. Using simultaneous recording from transfected or infected cells and control pyramidal cells, we found that PSD-95, similar to LTP, increases the amplitude and frequency of miniature EPSCs.

View Full Text PDF Listings View primary source full text article PDFs.

Jul
2002

Thiiranium (episulfonium) ions had been acknowledged as reaction intermediates for many years, but it was not until 1977 that Nicolaou demonstrated systematically that these reactive heterocyclic cations could be trapped by carboxylic acids to give lactones. In the years that followed this report, extensive research greatly extended the scope of this reaction, particularly with regard to the methods for generating thiiranium ions, the types of nucleophiles that are compatible with this reaction, and the selectivity involved in the cyclization reactions. For many years we have been using thiiranium ions for the synthesis of saturated heterocycles.

View Full Text PDF Listings View primary source full text article PDFs.

Jul
2002

The reduction of a series of hetero- and carbocyclic aromatic compounds under ammonia free conditions is described. By using LiDBB as a source of electrons, bis(methoxyethyl)amine (BMEA) as a protonating agent, and THF as a solvent, we were able to accomplish reductions more usually performed under Birch type conditions. Moreover, the use of these conditions was further enhanced by the tolerance of the reducing system toward reactive electrophiles that cannot be used successfully in ammonia.

View Full Text PDF Listings View primary source full text article PDFs.

Back to top