971 research outputs found
Synthesis of a Versatile Building Block for the Preparation of 6-N-Derivatized α-Galactosyl Ceramides: Rapid Access to Biologically Active Glycolipids
A concise route to the 6-azido-6-deoxy-α-galactosyl-phytosphingosine derivative 9 is reported. Orthogonal protection of the two amino groups allows elaboration of 9 into a range of 6-N-derivatized α-galactosyl ceramides by late-stage introduction of the acyl chain of the ceramide and the 6-N-group in the sugar head-group. Biologically active glycolipids 6 and 8 have been synthesized to illustrate the applicability of the approach
Ultrasound-induced emulsification of subcritical carbon dioxide/water with and without surfactant as a strategy for enhanced mass transport
Pulsed ultrasound was used to disperse a biphasic mixture of CO2/H2O in a 1 dm3 high-pressure reactor at 30 °C/80 bar. A view cell positioned in-line with the sonic vessel allowed observation of a turbid emulsion which lasted approximately 30 min after ceasing sonication. Within the ultrasound reactor, simultaneous CO2-continuous and H2O-continuous environments were identified. The hydrolysis of benzoyl chloride was employed to show that at similar power intensities, comparable initial rates (1.6 ± 0.3 × 10–3 s–1 at 95 W cm–2) were obtained with those reported for a 87 cm3 reactor (1.8 ± 0.2 × 10–3 s–1 at 105 W cm–2), demonstrating the conservation of the physical effects of ultrasound in high-pressure systems (emulsification induced by the action of acoustic forces near an interface). A comparison of benzoyl chloride hydrolysis rates and benzaldehyde mass transport relative to the non-sonicated, ‘silent’ cases confirmed that the application of ultrasound achieved reaction rates which were over 200 times faster, by reducing the mass transport resistance between CO2 and H2O. The versatility of the system was further demonstrated by ultrasound-induced hydrolysis in the presence of the polysorbate surfactant, Tween, which formed a more uniform CO2/H2O emulsion that significantly increased benzoyl chloride hydrolysis rates. Finally, pulse rate was employed as a means of slowing down the rate of hydrolysis, further illustrating how ultrasound can be used as a valuable tool for controlling reactions in CO2/H2O solvent mixtures
A novel twist on an old theme: β-Halovinylsilanes, a new elimination approach to oligoyne assembly
Academic drug discovery:Challenges and opportunities
There are many different approaches to drug discovery in academia, some of which are based broadly on the industrial model of discovering novel targets and then conducting screening within academic drug discovery centres to identify hit molecules. Here we describe our approach to drug discovery, which makes more efficient use of the capabilities and resources of the different stakeholders. Specifically, we have created a large portfolio of drug projects and conducted small amounts of derisking work to ensure projects are investment ready. In this feature we will describe this model, including its limitations and advantages, since we believe the ideas and concepts will be of interest to other academic institutions and consortia.</p
A structural perspective of how T cell receptors recognise the CD1 family of lipid antigen-presenting molecules
The CD1 family of antigen-presenting molecules adopt a Major Histocompatibility Complex class I (MHC-I) fold. Whereas MHC molecules present peptides, the CD1 family has evolved to bind self- and foreign-lipids. The CD1 family of antigen-presenting molecules comprises four members, CD1a, CD1b, CD1c, CD1d, that differ in their architecture around the lipid-binding cleft, thereby enabling diverse lipids to be accommodated. These CD1-lipid complexes are recognised by T cell receptors (TCRs) expressed on T cells, either through dual recognition of CD1 and lipid or in a new model whereby the TCR directly contacts CD1, thereby triggering an immune response. Chemical syntheses of lipid antigens, and analogues thereof, have been crucial in understanding the underlying specificity of T cell-mediated lipid immunity. This review will focus on our current understanding of how TCRs interact with CD1-lipid complexes, highlighting how it can be fundamentally different from TCR-MHC-peptide co-recognition
A structural perspective of how T cell receptors recognise the CD1 family of lipid antigen-presenting molecules
The CD1 family of antigen-presenting molecules adopt a Major Histocompatibility Complex class I (MHC-I) fold. Whereas MHC molecules present peptides, the CD1 family has evolved to bind self- and foreign-lipids. The CD1 family of antigen-presenting molecules comprises four members, CD1a, CD1b, CD1c, CD1d, that differ in their architecture around the lipid-binding cleft, thereby enabling diverse lipids to be accommodated. These CD1-lipid complexes are recognised by T cell receptors (TCRs) expressed on T cells, either through dual recognition of CD1 and lipid or in a new model whereby the TCR directly contacts CD1, thereby triggering an immune response. Chemical syntheses of lipid antigens, and analogues thereof, have been crucial in understanding the underlying specificity of T cell-mediated lipid immunity. This review will focus on our current understanding of how TCRs interact with CD1-lipid complexes, highlighting how it can be fundamentally different from TCR-MHC-peptide co-recognition
Ultrasound-induced CO<sub>2</sub> /H<sub>2</sub>O emulsions as a medium for clean product formation and separation : the Barbier reaction as a synthetic example
: Subcritical CO2/H2O (30 °C/80 bar) was
employed as a renewable solvent mixture in a 1 dm3
ultrasound reactor. As a representative synthetic transformation,
the metal-mediated Barbier allylation was used to
demonstrate the facility of formation and separation of the
homoallylic alcohol product. The chemoselectivity over the
competing aldehyde reduction could be improved by
deploying the biocompatible nonionic surfactant Tween 80,
a saturated salt aqueous phase, or by carrying out the reaction
at 60 °C/120 bar. All of these modifications led to an apparent
rate increase in the desired allylation. A range of substituted benzaldehydes afforded the corresponding homoallylic alcohols in
moderate to high yields. The presence of water constituted a necessary condition for efficient product formation, while CO2
provided an appropriate phase for clean product separation by exploiting a favorable homoallylic alcohol enrichment. In this way,
0.025 mol of homoallylic alcohol product could be isolated from the CO2 phase in 1 h, avoiding further extraction stages that
would typically require organic solvents
Effect of Drinking Rate on the Retention of Water or Milk Following Exercise-Induced Dehydration
This study investigated the effect of drinking rate on fluid retention of milk and water following exercise-induced dehydration. In Part A, 12 male participants lost 1.9% ± 0.3% body mass through cycle exercise on four occasions. Following exercise, plain water or low-fat milk equal to the volume of sweat lost during exercise was provided. Beverages were ingested over 30 or 90 min, resulting in four beverage treatments: water 30 min, water 90 min, milk 30 min, and milk 90 min. In Part B, 12 participants (nine males and three females) lost 2.0% ± 0.3% body mass through cycle exercise on four occasions. Following exercise, plain water equal to the volume of sweat lost during exercise was provided. Water was ingested over 15 min (DR15), 45 min (DR45), or 90 min (DR90), with either DR15 or DR45 repeated. In both trials, nude body mass, urine volume, urine specific gravity and osmolality, plasma osmolality, and subjective ratings of gastrointestinal symptoms were obtained preexercise and every hour for 3 hr after the onset of drinking. In Part A, no effect of drinking rate was observed on the proportion of fluid retained, but milk retention was greater (p
Preparation, characterisation and entrapment of a non-glycosidic threitol ceramide into liposomes for presentation to invariant natural killer T cells
Dendritic cells (DCs) are able to present glycolipids to invariant natural killer T (iNKT) cells in vivo. Very few compounds have been found to stimulate iNKT cells, and of these, the best characterised is the glycolipid a-galactosylceramide, which stimulates the production of large quantities of interferon-gamma (IFN-?) and interleukin-4 (IL-4). However, aGalCer leads to overstimulation of iNKT cells. It has been demonstrated that the aGalCer analogue, threitol ceramide (ThrCer 2), successfully activates iNKT cells and overcomes the problematic iNKT cell activation-induced anergy. In this study, ThrCer 2 has been inserted into the bilayers of liposomes composed of a neutral lipid, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), or dimethyldioctadecylammonium bromide (DDA), a cationic lipid. Incorporation efficiencies of ThrCer within the liposomes was 96% for DSPC liposomes and 80% for DDA liposomes, with the vesicle size (large multilamellar vs. small unilamellar vesicles) making no significant difference. Langmuir-Blodgett studies suggest that both DSPC and DDA stack within the monolayer co-operatively with the ThrCer molecules with no condensing effect. In terms of cellular responses, IFN-? secretion was higher for cells treated with small DDA liposomes compared with the other liposome formulations, suggesting that ThrCer encapsulation in this liposome formulation resulted in a higher uptake by DCs
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