37 research outputs found
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Liposome Enhanced Detection of Amyloid Protein Aggregates.
Thioflavin-T is used to image amyloid aggregates because of the excellent turn-on fluorescence properties, but binding affinities are low. By mounting multiple dye units on the surface of a vesicle, the binding affinity for α-synuclein fibrils is increased by three orders of magnitude, and the optical response is increased. Cooperative interactions of the dye headgroup and lipid with the protein provide a general strategy for the construction of multivalent amyloid probes based on vesicles.Engineering and Physical Sciences Research Council (EP/R005397/1 and EP/P008224/1)
Intelligent image-based in situ single-cell isolation
Quantifying heterogeneities within cell populations is important for many fields including cancer research and neurobiology; however, techniques to isolate individual cells are limited. Here, we describe a high-throughput, non-disruptive, and cost-effective isolation method that is capable of capturing individually targeted cells using widely available techniques. Using high-resolution microscopy, laser microcapture microscopy, image analysis, and machine learning, our technology enables scalable molecular genetic analysis of single cells, targetable by morphology or location within the sample.Peer reviewe
The Magnetoelastic Distortion of Multiferroic BiFeO in the Canted Antiferromagnetic State
Using THz spectroscopy, we show that the spin-wave spectrum of multiferroic
BiFeO in its high-field canted antiferromagnetic state is well described by
a spin model that violates rhombohedral symmetry. We demonstrate that the
monoclinic distortion of the canted antiferromagnetic state is induced by the
single-ion magnetoelastic coupling between the lattice and the two nearly
anti-parallel spins. The revised spin model for BiFeO contains two new
single-ion anisotropy terms that violate rhombohedral symmetry and depend on
the direction of the magnetic field.Comment: 28 pages (main & supplementary), 2 figures (main article), 15 figures
(supplementary material
CD62L (L-selectin) shedding for assessment of perioperative immune sensitivity in patients undergoing cardiac surgery with cardiopulmonary bypass
OBJECTIVE: To investigate the suitability of blood granulocyte and monocyte sensitivity, as measured by the quantity of different agonists required to induce CD62L shedding, for assessment of perioperative immune changes in patients undergoing cardiac surgery with cardiopulmonary bypass. METHODS: Patients scheduled for aortocoronary bypass grafting or for valve surgery were included in this prospective observational study. Blood samples were drawn before anesthesia induction, directly after surgery and 48 hours after anesthesia induction. We determined the concentration of two different inflammatory stimuli--lipoteichoic acid (LTA) and tumor necrosis factor alpha (TNF)--required to induce shedding of 50% of surface CD62L from blood granulocytes and monocytes. In parallel monocyte surface human leukocyte antigen (HLA)-DR, and plasma interleukin (IL)-8, soluble (s)CD62L, soluble (s)Toll-like receptor (TLR)-2 and ADAM17 quantification were used to illustrate perioperative immunomodulation. RESULTS: 25 patients were enrolled. Blood granulocytes and monocytes showed decreased sensitivity to the TLR 2/6 agonist Staphylococcus aureus LTA immediately after surgery (p = 0.001 and p = 0.004 respectively). In contrast, granulocytes (p = 0.01), but not monocytes (p = 0.057) displayed a decreased postoperative sensitivity to TNF. We confirmed the presence of a systemic inflammatory response and a decreased immune sensitivity in the post-surgical period by measuring significant increases in the perioperative plasma concentration of IL-8 (p </= 0.001) and sTLR (p = 0.004), and decreases in monocyte HLA-DR (p<0.001), plasma sCD62L (p </= 0.001). In contrast, ADAM17 plasma levels did not show significant differences over the observation period (p = 0.401). CONCLUSIONS: Monitoring granulocyte and monocyte sensitivity using the "CD62L shedding assay" in the perioperative period in cardiac surgical patients treated with the use of cardiopulmonary bypass reveals common changes in sensitivity to TLR2/6 ligands and to TNF stimulus. Further long-term follow-up studies will address the predictive value of these observations for clinical purposes
Black holes, gravitational waves and fundamental physics: a roadmap
The grand challenges of contemporary fundamental physicsâdark matter, dark energy, vacuum energy, inflation and early universe cosmology, singularities and the hierarchy problemâall involve gravity as a key component. And of all gravitational phenomena, black holes stand out in their elegant simplicity, while harbouring some of the most remarkable predictions of General Relativity: event horizons, singularities and ergoregions.
The hitherto invisible landscape of the gravitational Universe is being unveiled before our eyes: the historical direct detection of gravitational waves by the LIGO-Virgo collaboration marks the dawn of a new era of scientific exploration. Gravitational-wave astronomy will allow us to test models of black hole formation, growth and evolution, as well as models of gravitational-wave generation and propagation. It will provide evidence for event horizons and ergoregions, test the theory of General Relativity itself, and may reveal the existence of new fundamental fields. The synthesis of these results has the potential to radically reshape our understanding of the cosmos and of the laws of Nature.
The purpose of this work is to present a concise, yet comprehensive overview of the state of the art in the relevant fields of research, summarize important open problems, and lay out a roadmap for future progress. This write-up is an initiative taken within the framework of the European Action on 'Black holes, Gravitational waves and Fundamental Physics'
THĂSE POUR OBTENIR LE GRADE DE DOCTEUR Sous la direction de Dr. Mihai Barboiu Devant le jury composĂ© de SupramolĂ©culaire artificial water channels: from molecular design to membrane materialscette thĂšse couvre une Ă©tude fondamentale sur des canaux artificiels dâeau et sur des matĂ©riaux membranaires incorporant ces canaux
The work described in this thesis covers an in depth fundamental study of artificial water channels and of membrane materials incorporating these channels. Structured in four chapters, the thesis begins with a presentation of the state of the art in the field of biomimetic systems and membranes for water transport. The center of the described research work is the family of highly efficient and selective biological water transporter proteins, the Aquaporins. The second chapter presents the description of imidazole-quartet supramolecular artificial water channels. Structural and functional similarities with Aquaporins are discussed and based on several experimental methods. Single-solid state structures present very similar organization of confined water wires as found in their biological counterparts. Functional mimicry of water transport has been proved through stopped flow experiments in vesicular systems. Further characterization concerning water translocation mechanism and confined organization in lipid environments have been obtained through molecular dynamic simulations, while physical evidence of dipolar oriented water in lipid embedded channels has been provided by sum frequency generation experiments. The third chapter presents novel artificial water channels. New diol, tetrazacrown and tryarilamine based compounds have been described, with a main focus on design, synthesis, self-assembly and water transport properties. The last chapter makes the transition from the molecular systems to macroscopic membrane materials incorporating artificial water channels. Two different approaches have been described : thin film nanocomposite membranes based on the incorporation of imidazole-quartet nanoparticles in polyamide polymers and chemically grafted regenerated cellulose membrane through the use of custom monomers for the obtaining of artificial water channels. The membranes have been characterized through various imaging and analytical methods and their performances have been tested in reverse and forward osmosis experiments. The thesis is concluded with a general conclusion part, including perspectives for future developments.Le travail dĂ©crit dans cette thĂšse couvre une Ă©tude fondamentale sur des canaux artificiels dâeau et sur des matĂ©riaux membranaires incorporant ces canaux. StructurĂ© en quatre chapitres, la thĂšse commence par une prĂ©sentation de lâĂ©tat de lâart sur les systĂšmes biomimĂ©tiques de transport dâeau et des membranes biomimĂ©tiques. Au centre de tous ces travaux de recherche sont les protĂ©ines biologiques hautement efficaces et sĂ©lectives, les Aquaporines. Le deuxiĂšme chapitre prĂ©sente les canaux artificiels dâeau Ă base dâimidazole-quartet. Les similitudes structurelles et fonctionnelles avec les Aquaporines sont discutĂ©es et caractĂ©risĂ©es par plusieurs mĂ©thodes expĂ©rimentales. Les structures Ă lâĂ©tat solide obtenues Ă partir de monocristaux prĂ©sentent une organisation trĂšs similaire des I-quartets avec leurs homologues biologiques. Le biomimĂ©tisme fonctionnel du transport de lâeau a Ă©tĂ© dĂ©montrĂ© par des expĂ©riences cinĂ©tiques de transport Ă travers des systĂšmes vĂ©siculaires. Le mĂ©canisme de translocation de lâeau et lâorganisation confinĂ©e dans des environnements lipidiques a Ă©tĂ© confirmĂ© par des simulations dynamiques molĂ©culaires, tandis que la preuve physique de lâeau orientĂ©e dipolaire dans les canaux intĂ©grĂ©s aux lipides a Ă©tĂ© fournie par des expĂ©riences de spectroscopie IR polarisĂ©e. Le troisiĂšme chapitre prĂ©sente de nouveaux canaux dâeau artificiels en utilisant une stratĂ©gie dâauto-assemblage. De nouveaux composĂ©s Ă base de diol, de tĂ©trazacrown et de tryarilamine capables de transporter lâeau sont dĂ©crits. Le dernier chapitre dĂ©crits le passage du niveau molĂ©culaire aux matĂ©riaux membranaires macroscopiques incorporant des canaux dâeau artificiels. Deux configuration membranaires diffĂ©rentes ont Ă©tĂ© dĂ©crites : des membranes en couche mince par lâincorporation de nanoparticules Ă base dâimidazole dans des polymĂšres de polyamide et des membranes de la cellulose rĂ©gĂ©nĂ©rĂ©e chimiquement greffĂ©e par des monomĂšres de canaux dâeau artificiels. Les membranes ont Ă©tĂ© caractĂ©risĂ©es par diverses mĂ©thodes dâimagerie et dâanalyse et leurs performances ont Ă©tĂ© testĂ©es dans des expĂ©riences dâosmose inverse et de filtration dâosmose directe. La thĂšse est conclue avec une partie de conclusion gĂ©nĂ©rale, comprenant des perspectives pour les dĂ©veloppements futurs
Canaux d'eau artificielle supramoléculaires : de la conception moléculaire aux matériaux de membrane
Le travail dĂ©crit dans cette thĂšse couvre une Ă©tude fondamentale sur des canaux artificiels d'eau et sur des matĂ©riaux membranaires incorporant ces canaux. StructurĂ© en quatre chapitres, la thĂšse commence par une prĂ©sentation de l'Ă©tat de lâart sur les systĂšmes biomimĂ©tiques de transport d'eau et des membranes biomimĂ©tiques. Au centre de tous ces travaux de recherche sont les protĂ©ines biologiques hautement efficaces et sĂ©lectives, les Aquaporines. Le deuxiĂšme chapitre prĂ©sente les canaux artificiels d'eau Ă base d'imidazole-quartet. Les similitudes structurelles et fonctionnelles avec les Aquaporines sont discutĂ©es et caractĂ©risĂ©es par plusieurs mĂ©thodes expĂ©rimentales. Les structures Ă l'Ă©tat solide obtenues Ă partir de monocristaux prĂ©sentent une organisation trĂšs similaire des I-quartets avec leurs homologues biologiques. Le biomimĂ©tisme fonctionnel du transport de l'eau a Ă©tĂ© dĂ©montrĂ© par des expĂ©riences cinĂ©tiques de transport Ă travers des systĂšmes vĂ©siculaires. Le mĂ©canisme de translocation de l'eau et l'organisation confinĂ©e dans des environnements lipidiques a Ă©tĂ© confirmĂ© par des simulations dynamiques molĂ©culaires, tandis que la preuve physique de l'eau orientĂ©e dipolaire dans les canaux intĂ©grĂ©s aux lipides a Ă©tĂ© fournie par des expĂ©riences de spectroscopie IR polarisĂ©e. Le troisiĂšme chapitre prĂ©sente de nouveaux canaux d'eau artificiels en utilisant une stratĂ©gie d'auto-assemblage. De nouveaux composĂ©s Ă base de diol, de tĂ©trazacrown et de tryarilamine capables de transporter l'eau sont dĂ©crits. Le dernier chapitre dĂ©crits le passage du niveau molĂ©culaire aux matĂ©riaux membranaires macroscopiques incorporant des canaux d'eau artificiels. Deux configuration membranaires diffĂ©rentes ont Ă©tĂ© dĂ©crites: des membranes en couche mince par l'incorporation de nanoparticules Ă base d'imidazole dans des polymĂšres de polyamide et des membranes de la cellulose rĂ©gĂ©nĂ©rĂ©e chimiquement greffĂ©e par des monomĂšres de canaux d'eau artificiels. Les membranes ont Ă©tĂ© caractĂ©risĂ©es par diverses mĂ©thodes d'imagerie et d'analyse et leurs performances ont Ă©tĂ© testĂ©es dans des expĂ©riences d'osmose inverse et de filtration d'osmose directe. La thĂšse est conclue avec une partie de conclusion gĂ©nĂ©rale, comprenant des perspectives pour les dĂ©veloppements futurs.The work described in this thesis covers an in depth fundamental study of artificial water channels and of membrane materials incorporating these channels. Structured in four chapters, the thesis begins with a presentation of the state of the art in the field of biomimetic systems and membranes for water transport. The center of the described research work is the family of highly efficient and selective biological water transporter proteins, the Aquaporins. The second chapter presents the description of imidazole-quartet supramolecular artificial water channels. Structural and functional similarities with Aquaporins are discussed and based on several experimental methods. Single-solid state structures present very similar organization of confined water wires as found in their biological counterparts. Functional mimicry of water transport has been proved through stopped flow experiments in vesicular systems. Further characterization concerning water translocation mechanism and confined organization in lipid environments have been obtained through molecular dynamic simulations, while physical evidence of dipolar oriented water in lipid embedded channels has been provided by sum frequency generation experiments. The third chapter presents novel artificial water channels. New diol, tetrazacrown and tryarilamine based compounds have been described, with a main focus on design, synthesis, self-assembly and water transport properties. The last chapter makes the transition from the molecular systems to macroscopic membrane materials incorporating artificial water channels. Two different approaches have been described: thin film nanocomposite membranes based on the incorporation of imidazole-quartet nanoparticles in polyamide polymers and chemically grafted regenerated cellulose membrane through the use of custom monomers for the obtaining of artificial water channels. The membranes have been characterized through various imaging and analytical methods and their performances have been tested in reverse and forward osmosis experiments. The thesis is concluded with a general conclusion part, including perspectives for future developments
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Redox switching of an artificial transmembrane signal transduction system.
Transmission of chemical signals across lipid bilayer membranes can be achieved using membrane-anchored molecules, where molecular motion across the bilayer is controlled by switching the polarity of two different head groups. An external redox signal delivered by ascorbic acid was used to trigger membrane translocation in a synthetic transduction system.Engineering and Physical Sciences Research Council (EP/R005397/1)
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Transmembrane signal transduction by cofactor transport.
Information processing and cell signalling in biological systems relies on passing chemical signals across lipid bilayer membranes, but examples of synthetic systems that can achieve this process are rare. A synthetic transducer has been developed that triggers catalytic hydrolysis of an ester substrate inside lipid vesicles in response to addition of metal ions to the external vesicle solution. The output signal generated in the internal compartment of the vesicles is produced by binding of a metal ion cofactor to a head group on the transducer to form a catalytically competent complex. The mechanism of signal transduction is based on transport of the metal ion cofactor across the bilayer by the transducer, and the system can be reversibly switched between on and off states by adding cadmium(ii) and ethylene diamine tetracarboxylic acid input signals respectively. The transducer is also equipped with a hydrazide moiety, which allows modulation of activity through covalent conjugation with aldehydes. Conjugation with a sugar derivative abolished activity, because the resulting hydrazone is too polar to cross the bilayer, whereas conjugation with a pyridine derivative increased activity. Coupling transport with catalysis provides a straightforward mechanism for generating complex systems using simple components