281 research outputs found
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Fragment-based approaches to TB drugs.
Tuberculosis is an infectious disease associated with significant mortality and morbidity worldwide, particularly in developing countries. The rise of antibiotic resistance in Mycobacterium tuberculosis (Mtb) urgently demands the development of new drug leads to tackle resistant strains. Fragment-based methods have recently emerged at the forefront of pharmaceutical development as a means to generate more effective lead structures, via the identification of fragment molecules that form weak but high quality interactions with the target biomolecule and subsequent fragment optimization. This review highlights a number of novel inhibitors of Mtb targets that have been developed through fragment-based approaches in recent years.Croucher Foundation and Cambridge Overseas Trust (Croucher Cambridge International Scholarship
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Applications of Microdroplet Technology for Algal Biotechnology
Background: Microfluidics allows manipulation of small volumes of fluids through channels with dimensions of tens to hundreds of micrometres. Microdroplet technology is a form of microfluidics in which small (10-200 μm diameter) monodispersed aqueous droplets are generated, manipulated and analysed in various ways. This multidisciplinary field provides an exciting new platform for single-cell studies of both eukaryotic microalgae and cyanobacteria, with considerable potential for enhancing algal biotechnology.
Methods: Growth of several species of microalgae has been studied in detail using microfluidics and microdroplets, and individual cells have been screened and sorted according to lipid content or ethanol production. Here we provide an overview of the devices, and the range of technological advances that are being pursued.
Conclusion: Microdroplet technology is an emerging technology platform that can be used in a variety of applications, including monitoring of growth characteristics at the single-cell level and high-throughput screening of algal populations. Microdroplet platforms are being developed that will allow determination of individual cell characteristics to allow screening across a population, and thus to identify and select candidate cells for biotechnological feedstocks. As the potential of this emerging technical platform is recognized, the technology will become more accessible, so that it can soon be adopted and used by researchers, without the need for specialized prior knowledge of microfluidics or expensive equipment. The platform is amenable for use with species of both microalgae and cyanobacteria.SAC acknowledges the funding from EC within the EU FP7 DEMA project, grant agreement n°309086. RB was supported by a doctoral training grant from the Engineering and Physical Sciences Research Council (EPSRC) of the UK.This is the author accepted manuscript. The final version is available from Bentham Science via http://dx.doi.org/10.2174/221155010566616020200255
Reciprocity and resilience: teaching and learning sustainable social enterprise through gaming
Against a backdrop of increased global environmental and economic uncertainty, the resilience and sustainability of urban communities is a paramount concern for decision makers. The work presented here aims to explore how teaching and learning around transition initiatives, based upon social enterprise and reciprocity, might be supported by game theory and strategy simulation environments. Key elements for this are the coevolutionary nature of internal and external organisational contexts. The gaming prototype developed here (Exploring Community Resilience, ExCoRe)is based upon an extension of the Prisoner’s Dilemma as a medium for active learning, but is enacted through a multi-player and dynamic environment. The key learning objectives for the game are to introduce a broad concept of reciprocity and collaboration on a systems level, and the importance of an emergent and responsive ‘learning strategy’ for new start-ups and enterprises. The static nature of the traditional strengths, weaknesses, opportunities, and threats (SWOT) approach is challenged and students are encouraged to appreciate, through establishing game strategy, a much more fluid and dynamic relationship between internal and external environments
Surface-immobilised micelles via cucurbit[8]uril-rotaxanes for solvent-induced burst release.
The fabrication, characterisation and controlled burst release of naphthol-functionalised micellar (NFM) nanostructures, which were grafted onto gold surfaces through cucurbit[8]uril (CB[8]) mediated host-guest interactions are described. NFMs undergo a facile change in morphology from micelles to diblock copolymers in direct response to exposure to organic solvents, including tetrahydrofuran (THF), toluene and chloroform. This induced transition in conformation lends itself to potential applications including nanocarriers for triggered burst-release of guest molecules. Nile Red was investigated as a NFM encapsulated model hydrophobic cargo inside the surface-attached micelles, which could be fully released upon exposure to THF as measured by both atomic force microscopy and UV/vis spectroscopy.C. Hu thanks BP for supporting this work and Hughes Hall
College Cambridge for a student scholarship. Y. Zheng was
supported by an ERC starting investigator grant (ASPiRe
240629). Z. Yu is supported by an EPSRC grant (EP/H046593/1).This is the final version. It first appeared at http://pubs.rsc.org/en/Content/ArticleLanding/2015/CC/C5CC00121H#!divAbstract
Selective Targeting of the TPX2 Site of Importin-α Using Fragment-Based Ligand Design.
Protein-protein interactions are difficult therapeutic targets, and inhibiting pathologically relevant interactions without disrupting other essential ones presents an additional challenge. Herein we report how this might be achieved for the potential anticancer target, the TPX2-importin-α interaction. Importin-α is a nuclear transport protein that regulates the spindle assembly protein TPX2. It has two binding sites--major and minor-to which partners bind. Most nuclear transport cargoes use the major site, whereas TPX2 binds principally to the minor site. Fragment-based approaches were used to identify small molecules that bind importin-α, and crystallographic studies identified a lead series that was observed to bind specifically to the minor site, representing the first ligands specific for this site. Structure-guided synthesis informed the elaboration of these fragments to explore the source of ligand selectivity between the minor and major sites. These ligands are starting points for the development of inhibitors of this protein-protein interaction.This work was supported by the University of Cambridge Cancer Research UK Medicinal Chemistry training program and Medical Research Council grant U105178939 (to M.S.).This is the final published version. It first appeared at http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201500014/abstrac
Microdroplet fabrication of silver–agarose nanocomposite beads for SERS optical accumulation
Microdroplets have been used as reactors for the fabrication of agarose beads with high uniformity in shape and size, and densely loaded with silver ions, which were subsequently reduced into nanoparticles using hydrazine. The resulting nanocomposite beads not only display a high plasmonic activity, but can also trap/concentrate analytes, which can be identified by means of surface-enhanced Raman scattering (SERS) spectroscopy. The size of the beads is such that it allows the detection of a single bead under a conventional optical microscope, which is very useful to reduce the amount of material required for SERS detectio
Disrupting the Constitutive, Homodimeric Protein-Protein Interface in CK2β Using a Biophysical Fragment-Based Approach.
Identifying small molecules that induce the disruption of constitutive protein-protein interfaces is a challenging objective. Here, a targeted biophysical screening cascade was employed to specifically identify small molecules that could disrupt the constitutive, homodimeric protein-protein interface within CK2β. This approach could potentially be applied to achieve subunit disassembly of other homo-oligomeric proteins as a means of modulating protein function.This research was supported by the Agency for Science, Technology and Research (A*STAR) Singapore (Ph.D. sponsorship, W.G.S.) and the Wellcome Trust Strategic Award (090340/Z/09/Z)
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Mass Spectrometry Reveals Protein Kinase CK2 High-Order Oligomerization via the Circular and Linear Assembly.
CK2 is an intrinsically active protein kinase that is crucial for cellular viability. However, conventional kinase regulatory mechanisms do not apply to CK2, and its mode of regulation remains elusive. Interestingly, CK2 is known to undergo reversible ionic-strength-dependent oligomerization. Furthermore, a regulatory mechanism based on autoinhibitory oligomerization has been postulated on the basis of the observation of circular trimeric oligomers and linear CK2 assemblies in various crystal structures. Here, we employ native mass spectrometry to monitor the assembly of oligomeric CK2 species in an ionic-strength-dependent manner. A subsequent combination of ion mobility spectrometry-mass spectrometry and hydrogen-deuterium exchange mass spectrometry techniques was used to analyze the conformation of CK2 oligomers. Our findings support ionic-strength-dependent CK2 oligomerization, demonstrate the transient nature of the α/β interaction, and show that CK2 oligomerization proceeds via both the circular and linear assembly.This research was supported by the Wellcome Trust Strategic Award (090340/Z/09/Z), the Agency for Science Technology and Research (A*STAR) Singapore (Ph.D. sponsorship, W.G.S.), and the Croucher Foundation and the Cambridge Overseas Trust (Croucher Cambridge International Scholarship, D.S.-H.C).This is the author accepted manuscript. The final version is available from the American Chemical Society via http://dx.doi.org/10.1021/acschembio.6b0006
Hydrophilic PDMS microchannels for high-throughput formation of oil-in-water microdroplets and water-in-oil-in-water double emulsions
Here we present a novel surface modification method based on the sequential layer-by-layer deposition of polyelectrolytes yielding hydrophilic microchannels in PDMS-based microfluidic devices. The coatings are long-term stable and allow for the generation of monodisperse oil-in-water microdroplets even several months after the channel surface treatment. Due to the robustness of the polyelectrolyte multilayers ultra-high flow rates can be applied, making high-throughput droplet formation in the jetting mode possible. Furthermore, we successfully used our method to selectively modify the surface properties in certain areas of assembled microchannels. The resulting partially hydrophilic, partially hydrophobic microfluidic devices allow for the production of monodisperse water-in-oil-in-water double emulsions.<br/
Droplet microfuidics for the highly controlled synthesis of branched gold nanoparticles
The synthesis of anisotropic metallic nanoparticles (NPs) has been a feld of intense and challenging
research in the past decade. In this communication, we report on the reproducible and highly
controllable synthesis of monodisperse branched gold nanoparticles in a droplet-based microfuidics
platform. The process has been automated by adapting two diferent bulk synthetic strategies to
microdroplets, acting as microreactors, for NP synthesis: a surfactant-free synthesis and a surfactantassisted synthesis. Microdroplets were generated in two diferent microfuidic devices designed to
accommodate the requirements of both bulk syntheses. The epitaxial growth of AuNSTs inside the
microdroplets allowed for a fne control of reagent mixing and local concentrations during particle
formation. This is the frst time branched gold NPs have been synthesised in a microfuidics platform.
The monodispersity of the product was comparable to the synthesis in bulk, proving the potential
of this technology for the continuous synthesis of high quality anisotropic NPs with improved
reproducibility.8FAPESP – Fundação de Amparo à Pesquisa Do Estado De São Paulo2015/01685-2; 2016/02414-
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