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  • ItemOpen AccessPublished version Peer-reviewed
    SpoVT: From Fine-Tuning Regulator in Bacillus subtilis to Essential Sporulation Protein in Bacillus cereus.
    (Frontiers Media SA, 2016) Eijlander, Robyn T; Holsappel, Siger; de Jong, Anne; Ghosh, Abhinaba; Christie, Graham; Kuipers, Oscar P; Christie, Graham [0000-0001-7177-9646]
    Sporulation is a highly sophisticated developmental process adopted by most Bacilli as a survival strategy to withstand extreme conditions that normally do not support microbial growth. A complicated regulatory cascade, divided into various stages and taking place in two different compartments of the cell, involves a number of primary and secondary regulator proteins that drive gene expression directed toward the formation and maturation of an endospore. Such regulator proteins are highly conserved among various spore formers. Despite this conservation, both regulatory and phenotypic differences are observed between different species of spore forming bacteria. In this study, we demonstrate that deletion of the regulatory sporulation protein SpoVT results in a severe sporulation defect in Bacillus cereus, whereas this is not observed in Bacillus subtilis. Although spores are initially formed, the process is stalled at a later stage in development, followed by lysis of the forespore and the mother cell. A transcriptomic investigation of B. cereus ΔspoVT shows upregulation of genes involved in germination, potentially leading to premature lysis of prespores formed. Additionally, extreme variation in the expression of species-specific genes of unknown function was observed. Introduction of the B. subtilis SpoVT protein could partly restore the sporulation defect in the B. cereus spoVT mutant strain. The difference in phenotype is thus more than likely explained by differences in promoter targets rather than differences in mode of action of the conserved SpoVT regulator protein. This study stresses that evolutionary variances in regulon members of sporulation regulators can have profound effects on the spore developmental process and that mere protein homology is not a foolproof predictor of similar phenotypes.
  • ItemOpen AccessAccepted version Peer-reviewed
    Proteins Encoded by the gerP Operon Are Localized to the Inner Coat in Bacillus cereus Spores and Are Dependent on GerPA and SafA for Assembly.
    (American Society for Microbiology, 2018-07-15) Ghosh, Abhinaba; Manton, James D; Mustafa, Amin R; Gupta, Mudit; Ayuso-Garcia, Alejandro; Rees, Eric J; Christie, Graham; Manton, James [0000-0001-9260-3156]; Rees, Eric [0000-0001-7478-5961]; Christie, Graham [0000-0001-7177-9646]
    The germination of Bacillus spores is triggered by certain amino acids and sugar molecules which permeate the outermost layers of the spore to interact with receptor complexes that reside in the inner membrane. Previous studies have shown that mutations in the hexacistronic gerP locus reduce the rate of spore germination, with experimental evidence indicating that the defect stems from reduced permeability of the spore coat to germinant molecules. Here, we use the ellipsoid localization microscopy technique to reveal that all six Bacillus cereus GerP proteins share proximity with cortex-lytic enzymes within the inner coat. We also reveal that the GerPA protein alone can localize in the absence of all other GerP proteins and that it has an essential role for the localization of all other GerP proteins within the spore. Its essential role is also demonstrated to be dependent on SafA, but not CotE, for localization, which is consistent with an inner coat location. GerP-null spores are shown also to have reduced permeability to fluorescently labeled dextran molecules compared to wild-type spores. Overall, the results support the hypothesis that the GerP proteins have a structural role within the spore associated with coat permeability.IMPORTANCE The bacterial spore coat comprises a multilayered proteinaceous structure that influences the distribution, survival, and germination properties of spores in the environment. The results from the current study are significant since they increase our understanding of coat assembly and architecture while adding detail to existing models of germination. We demonstrate also that the ellipsoid localization microscopy (ELM) image analysis technique can be used as a novel tool to provide direct quantitative measurements of spore coat permeability. Progress in all of these areas should ultimately facilitate improved methods of spore control in a range of industrial, health care, and environmental sectors.
  • ItemOpen AccessPublished version Peer-reviewed
    ELM: super-resolution analysis of wide-field images of fluorescent shell structures.
    (IOP Publishing, 2018-05-16) Manton, James D; Xiao, Yao; Turner, Robert D; Christie, Graham; Rees, Eric J; Manton, James [0000-0001-9260-3156]; Christie, Graham [0000-0001-7177-9646]; Rees, Eric [0000-0001-7478-5961]
    It is often necessary to precisely quantify the size of specimens in biological studies. When measuring feature size in fluorescence microscopy, significant biases can arise due to blurring of its edges if the feature is smaller than the diffraction limit of resolution. This problem is avoided if an equation describing the feature's entire image is fitted to its image data. In this paper we present open-source software, ELM, which uses this approach to measure the size of spheroidal or cylindrical fluorescent shells with a precision of around 10 nm. This has been used to measure coat protein locations in bacterial spores and cell wall diameter in vegetative bacilli, and may also be valuable in microbiological studies of algae, fungi and viruses. ELM is available for download at https://github.com/quantitativeimaging/ELM.
  • ItemOpen AccessAccepted version Peer-reviewed
    Errata: Heat exchanger network cleaning scheduling: From optimal control to mixed-integer decision making
    (Elsevier BV, 2018) Adloor, SD; Ismaili, RA; Wilson, DI; Vassiliadis, VS; Wilson, Ian [0000-0003-3950-9165]; Vassiliadis, Vassili [0000-0002-5415-7551]
    Errata to the article by Al Ismaili et al. [1], on the optimal scheduling of cleaning actions for Heat Exchanger Networks under fouling, are presented. Errors present in the equations of the Pontryagin Minimum Principle analysis of the original article are indicated and rectified. It is noted that despite these errors, there is no change to the conclusions of the analysis given in Al Ismaili et al. [1].
  • ItemOpen AccessAccepted version Peer-reviewed
    On the differing growth mechanisms of black-smoker and Lost City-type hydrothermal vents.
    (The Royal Society, 2017-09) Cardoso, Silvana SS; Cartwright, Julyan HE; Cardoso, Silvana SS [0000-0003-0417-035X]; Cartwright, Julyan HE [0000-0001-7392-0957]
    Black smokers and Lost City-type springs are varieties of hydrothermal vents on the ocean floors that emit hot, acidic water and cool, alkaline water, respectively. While both produce precipitation structures as the issuing fluid encounters oceanic water, Lost City-type hydrothermal vents in particular have been implicated in the origin of life on the Earth. We present a parallel-velocity flow model for the radius and flow rate of a cylindrical jet of fluid that forms the template for the growth of a tube precipitated about itself and we compare the solution with previous laboratory experimental results from growth of silicate chemical gardens. We show that when the growth of the solid structure is determined by thermal diffusion, fluid flow is slow at the solid-liquid contact. However, in the case of chemical diffusive transport, the fluid jet effectively drags the liquid in the pores of the solid precipitate. These findings suggest a continuum in the diffusive growth rate of hydrothermal vent structures, where Lost City-type hydrothermal vents favour contact between the vent fluid and the external seawater. We explore the implications for the road to life.
  • ItemOpen AccessAccepted version Peer-reviewed
    Operando magnetic resonance studies of phase behaviour and oligomer accumulation within catalyst pores during heterogeneous catalytic ethene oligomerization
    (Elsevier BV, 2018) Baker, L; Renshaw, MP; Mantle, MD; Sederman, AJ; Wain, AJ; Gladden, LF; Mantle, Mick [0000-0001-7977-3812]; Sederman, Andy [0000-0002-7866-5550]; Gladden, Lynn [0000-0001-9519-0406]
    Two-dimensional 1H magnetic resonance imaging and spatially-resolved 1H magnetic resonance spectroscopy and diffusion measurements were recorded as a function of time-on-stream within a fixed-bed reactor to provide direct measurements of the progress of the heterogeneous catalytic oligomerization of ethene occurring over a 1 wt% Ni-Al2O3-SiO2 catalyst. The catalyst bed was of internal diameter 2 cm; magnetic resonance measurements were recorded over a bed length of 5.5 cm. Experiments were conducted at a temperature and pressure of 110 °C and 29 bara, respectively, with continuous downflow of ethene at a flowrate of 0.78 L h-1. During conversion the accumulation of 1H-containing species within the catalyst pellets was imaged, and spatially-resolved 1H NMR spectra were recorded at 1 mm intervals along the length of the reactor. Diffusion-filtered 1D chemical shift imaging was used to discriminate between gas- and liquid-phase species along the length of the reactor at 1 mm intervals. Finally, spectrally-encoded pulsed field gradient measurements of molecular diffusion were employed to infer the molecular composition of the gas and liquid phases and to identify populations of these phases inside and external to the pore space of the catalyst pellets; these measurements were spatially-resolved along the length of the reactor, with data being averaged over sections of height 4 mm. The results are consistent with oligomers of carbon number C20 and greater existing within the pores of the catalyst pellets which act to block the pore space, thereby deactivating the catalyst.
  • ItemOpen AccessAccepted version Peer-reviewed
    Energy of Liposome Patch Adhesion to the Pipet Glass Determined by Confocal Fluorescence Microscopy.
    (American Chemical Society (ACS), 2016-11-17) Nakayama, Yoshitaka; Slavchov, Radomir I; Bavi, Navid; Martinac, Boris; Slavchov, Radomir [0000-0002-4639-1225]
    The formation of the gigaseal in the patch clamp technique is dependent on the adhesion between the cell or liposome membrane and the glass pipet. The adhesion results in a capillary force causing creep of the patch membrane up the pipet. The membrane can be immobilized by counteracting the capillary force by positive pressure applied to the patch pipet. We use this phenomenon to develop a method for static measurement of the adhesion free energy of the lipid bilayer to the glass. Confocal fluorescent microscopy is used to track the bilayer creep inside the pipet and measure the immobilization pressure at various salt concentrations and pH. The adhesion energy is simply related to this pressure. For the studied phospholipid bilayers, its values were in the 0.3-0.7 mJ/m2 range, increased with salt concentration, and had a maximum as a function of pH. This method offers a way to measure bilayer-glass adhesion energy in patch clamp experiments that is more precise than dynamic methods.
  • ItemOpen AccessPublished version Peer-reviewed
    Predicting the structures and associated phase transition mechanisms in disordered crystals via a combination of experimental and theoretical methods.
    (Royal Society of Chemistry (RSC), 2018-10-26) Ruggiero, Michael T; Kölbel, Johanna; Li, Qi; Zeitler, J Axel; Ruggiero, Michael [0000-0003-1848-2565]; Li, Qi [0000-0003-0841-2758]; Zeitler, Axel [0000-0002-4958-0582]
    Disordered materials make up a large proportion of condensed phase systems, but the difficulties in describing their structures and molecular dynamics limit their potential applications. Disordered crystalline systems, also known as plastic crystals, offer a unique perspective into these factors because the systems retain a degree of crystallinity, reducing the degrees of freedom that must be explored when interpreting the results. However, while disordered crystals do diffract X-rays, it is difficult to fully resolve meaningful crystalline structures, with the best scenario resulting in lattice parameters. In this study, we use a combination of experimental terahertz time-domain spectroscopy, and theoretical solid-state ab initio density functional theory and molecular dynamics simulations to fully elucidate the structures and associated dynamics of organic molecular solids. The results highlight that this combination provides a complete description of the energetic and mechanistic pathways involved in the formation of disordered crystals, and highlights the importance of low-frequency dynamics in their properties. Finally, with structures fully determined and validated by the experimental results, recent progress into anharmonic calculations, namely the quasi-harmonic approximation method, enables full temperature and pressure-dependent properties to be understood within the framework of the potential energy hyper-surface structure.
  • ItemOpen AccessPublished version Peer-reviewed
    Phylogeographic diversity and mosaicism of the Helicobacter pylori tfs integrative and conjugative elements.
    (2018-01-26) Delahay, Robin M; Croxall, Nicola J; Stephens, Amberley D; Delahay, Robin M [0000-0002-7108-565X]; Stephens, Amberley D [0000-0002-7303-6392]
  • ItemOpen AccessPublished version Peer-reviewed
    Linking attractive interactions and confinement to the rheological response of suspended particles close to jamming.
    (Springer Science and Business Media LLC, 2018) Jones, Michael A; Ness, Christopher; Jones, Michael A [0000-0002-6730-9964]; Ness, Christopher [0000-0002-0842-2537]
    We study the response to simple shear start-up of an overdamped, athermal assembly of particles with tuneable attractive interactions. We focus on volume fractions close to the jamming point, where such systems can become disordered elastoplastic solids. By systematically varying the strength of the particle-particle attraction and the volume fraction, we demonstrate how cohesion and confinement individually contribute to the shear modulus and yield strain of the material. The results provide evidence for the influence of binding agents on the rheology of dense, athermal suspensions and describe a set of handles with which the macroscopic properties of such materials can be engineered.
  • ItemOpen AccessPublished version Peer-reviewed
    Concomitant polymorphism and the martensitic-like transformation of an organic crystal.
    (Royal Society of Chemistry (RSC), 2017-11-01) Ruggiero, Michael T; Axel Zeitler, J; Korter, Timothy M; Ruggiero, Michael T [0000-0003-1848-2565]; Axel Zeitler, J [0000-0002-4958-0582]; Korter, Timothy M [0000-0002-0398-5680]
    Crystalline polymorphism is a phenomenon that occurs in many molecular solids, resulting in a diverse range of possible bulk structures. Temperature and pressure can often be used to thermodynamically control which crystal form is preferred, and the associated transitions between polymorphic phases are often discontinuous and complete. N-Methyl-4-carboxypyridinium chloride is a solid that undergoes an apparent continuous temperature-dependent phase transition from an orthorhombic to a monoclinic polymorph. However, a hybrid characterization approach using single-crystal X-ray diffraction, terahertz time-domain spectroscopy, and solid-state density functional theory reveals the transformation to be actually a slowly changing ratio of the two discrete polymorphic forms. The potential energy surface of this process can be directly accessed using terahertz radiation, and the data show that a very low barrier (43.3 J mol-1) exists along the polymorph transformation coordinate.
  • ItemOpen AccessPublished version Peer-reviewed
    Dendritic cell immunotherapy followed by cART interruption during HIV-1 infection induces plasma protein markers of cellular immunity and neutrophil recruitment.
    (Public Library of Science (PLoS), 2018) van den Ham, Henk-Jan; Cooper, Jason D; Tomasik, Jakub; Bahn, Sabine; Aerts, Joeri L; Osterhaus, Albert DME; Gruters, Rob A; Andeweg, Arno C; DC-TRN trial investigators; van den Ham, Henk-Jan [0000-0001-8582-5404]
    OBJECTIVES: To characterize the host response to dendritic cell-based immunotherapy and subsequent combined antiretroviral therapy (cART) interruption in HIV-1-infected individuals at the plasma protein level. DESIGN: An autologous dendritic cell (DC) therapeutic vaccine was administered to HIV-infected individuals, stable on cART. The effect of vaccination was evaluated at the plasma protein level during the period preceding cART interruption, during analytical therapy interruption and at viral reactivation. Healthy controls and post-exposure prophylactically treated healthy individuals were included as controls. METHODS: Plasma marker ('analyte') levels including cytokines, chemokines, growth factors, and hormones were measured in trial participants and control plasma samples using a multiplex immunoassay. Analyte levels were analysed using principle component analysis, cluster analysis and limma. Blood neutrophil counts were analysed using linear regression. RESULTS: Plasma analyte levels of HIV-infected individuals are markedly different from those of healthy controls and HIV-negative individuals receiving post-exposure prophylaxis. Viral reactivation following cART interruption also affects multiple analytes, but cART interruption itself only has only a minor effect. We find that Thyroxine-Binding Globulin (TBG) levels and late-stage neutrophil numbers correlate with the time off cART after DC vaccination. Furthermore, analysis shows that cART alters several regulators of blood glucose levels, including C-peptide, chromogranin-A and leptin. HIV reactivation is associated with the upregulation of CXCR3 ligands. CONCLUSIONS: Chronic HIV infection leads to a change in multiple plasma analyte levels, as does virus reactivation after cART interruption. Furthermore, we find evidence for the involvement of TBG and neutrophils in the response to DC-vaccination in the setting of HIV-infection.
  • ItemOpen AccessPublished version Peer-reviewed
    Schizophrenia-risk and urban birth are associated with proteomic changes in neonatal dried blood spots.
    (Springer Science and Business Media LLC, 2017-12-18) Cooper, Jason D; Ozcan, Sureyya; Gardner, Renee M; Rustogi, Nitin; Wicks, Susanne; van Rees, Geertje F; Leweke, F Markus; Dalman, Christina; Karlsson, Håkan; Bahn, Sabine; Ozcan, Sureyya [0000-0002-9371-3696]; van Rees, Geertje F [0000-0002-9431-0653]; Leweke, F Markus [0000-0002-8163-195X]; Dalman, Christina [0000-0002-3579-2357]; Karlsson, Håkan [0000-0001-5985-7330]
    In the present study, we tested whether there were proteomic differences in blood between schizophrenia patients after the initial onset of the disorder and controls; and whether those differences were also present at birth among neonates who later developed schizophrenia compared to those without a psychiatric admission. We used multiple reaction monitoring mass spectrometry to quantify 77 proteins (147 peptides) in serum samples from 60 first-onset drug-naive schizophrenia patients and 77 controls, and 96 proteins (152 peptides) in 892 newborn blood-spot (NBS) samples collected between 1975 and 1985. Both serum and NBS studies showed significant alterations in protein levels. Serum results revealed that Haptoglobin and Plasma protease C1 inhibitor were significantly upregulated in first-onset schizophrenia patients (corrected P < 0.05). Alpha-2-antiplasmin, Complement C4-A and Antithrombin-III were increased in first-onset schizophrenia patients (uncorrected P-values 0.041, 0.036 and 0.013, respectively) and also increased in newborn babies who later develop schizophrenia (P-values 0.0058, 0.013 and 0.044, respectively). We also tested whether protein abundance at birth was associated with exposure to an urban environment during pregnancy and found highly significant proteomic differences at birth between urban and rural environments. The prediction model for urbanicity had excellent predictive performance in both discovery (area under the receiver operating characteristic curve (AUC) = 0.90) and validation (AUC = 0.89) sample sets. We hope that future biomarker studies based on stored NBS samples will identify prognostic disease indicators and targets for preventive measures for neurodevelopmental conditions, particularly those with onset during early childhood, such as autism spectrum disorder.
  • ItemOpen AccessPublished version Peer-reviewed
    Modelling of pastes as viscous soils – Lubricated squeeze flow
    (Elsevier BV, 2018) Patel, MJ; Blackburn, S; Wilson, DI; Wilson, Ian [0000-0003-3950-9165]
    Highly filled suspensions (or pastes) present complex rheological behaviour and squeeze flow testing is used frequently for rheological characterisation. The extent to which liquid phase migration (LPM) occurs in such tests, and the influence of material extruded from between the plates, was investigated in experiments supported by detailed modelling based on soil mechanics approaches. Lubricated squeeze flow (LSF) tests were conducted on a model saturated ballotini paste prepared with a viscous Newtonian binder, at plate speeds spanning two decades. The tests were simulated using a two-dimensional (2 D) axisymmetric finite element model with adaptive remeshing to circumvent mesh distortion. The paste was modelled as a viscoplastic soil (Drucker-Prager) to capture both rate-dependent effects at high shear rates and LPM at low shear rates. Capillary pressure was applied at the evolving free surface and the plate surfaces were modelled as frictionless for simplicity. Reasonable agreement was obtained between the measured and predicted squeezing pressure profiles at the highest solids volume fraction tested (ϕs = 60%). Agreement was poor at the lowest ϕs (52.5%), which was due to this paste formulation behaving as a suspension/slurry without a distinct yield stress. For the first time, the predicted squeezing pressure was resolved into components using an energy analysis. The squeezing pressure was dominated by the work required to deform the paste in the gap. This result is specific to highly viscoplastic pastes and persisted to small plate separations when most of the sample lay outside the plates. Characterisation of the yield stress from the ‘shoulder’ in the squeezing pressure profile was reasonably accurate at h/h0 ≥ 96% (9% estimated error). LPM was neither observed nor predicted at the plate speeds tested, despite the favourable pore pressure driving force, due to the high binder viscosity and the zero dilation angle in the simulations. The flow field was characterised using a novel flow mode parameter derived from the shear rate tensor. The paste was predicted to undergo pure biaxial extension between the smooth plates, and for the first time was predicted to undergo pure uniaxial extension external to the plates and (briefly) pure shear at the boundary.
  • ItemOpen AccessAccepted version Peer-reviewed
    Adsorption of Ions at Uncharged Insoluble Monolayers.
    (American Chemical Society (ACS), 2016-09-06) Peshkova, Tatyana V; Minkov, Ivan L; Tsekov, Roumen; Slavchov, Radomir I; Slavchov, Radomir [0000-0002-4639-1225]
    A method is proposed for the experimental determination of the adsorption of inorganic electrolytes at a surface covered with insoluble surfactant monolayer. This task is complicated by the fact that the change of the salt concentration alters both chemical potentials of the electrolyte and the surfactant. Our method resolves the question by combining data for the surface pressure versus area of the monolayer at several salt concentrations with data for the equilibrium spreading pressure of crystals of the surfactant (used to fix a standard state). We applied the method to alcohols spread at the surface of concentrated halide solutions. The measured salt adsorption is positive and has nonmonotonic dependence on the area per surfactant molecule. For the liquid expanded film, depending on the concentration, there is one couple of ions adsorbed per each 3-30 surfactant molecules. We analyzed which ion, the positive or the negative, stands closer to the surface, by measuring the effect of NaCl on the Volta potential of the monolayer. The potentiometric data suggest that Na(+) is specifically adsorbed, while Cl(-) remains in the diffuse layer, i.e., the surface is positively charged. The observed reverse Hofmeister series of the adsorptions of NaF, NaCl, and NaBr suggests the same conclusion holds for all these salts. The force that causes the adsorption of Na(+) seems to be the interaction of the ion with the dipole moment of the monolayer.
  • ItemOpen AccessPublished version Peer-reviewed
    Continuous synthesis of tuneable sized silver nanoparticles: Via a tandem seed-mediated method in coiled flow inverter reactors
    (Royal Society of Chemistry (RSC), 2018) Wu, KJ; Torrente-Murciano, L

    Size control of metal nanoparticles is essential to achieve accurate adjustment of their unique chemical and physical properties.

  • ItemOpen AccessAccepted version Peer-reviewed
    Unifying model for random matrix theory in arbitrary space dimensions.
    (American Physical Society (APS), 2018-03) Cicuta, Giovanni M; Krausser, Johannes; Milkus, Rico; Zaccone, Alessio; Zaccone, Alessio [0000-0002-6673-7043]
    A sparse random block matrix model suggested by the Hessian matrix used in the study of elastic vibrational modes of amorphous solids is presented and analyzed. By evaluating some moments, benchmarked against numerics, differences in the eigenvalue spectrum of this model in different limits of space dimension d, and for arbitrary values of the lattice coordination number Z, are shown and discussed. As a function of these two parameters (and their ratio Z/d), the most studied models in random matrix theory (Erdos-Renyi graphs, effective medium, and replicas) can be reproduced in the various limits of block dimensionality d. Remarkably, the Marchenko-Pastur spectral density (which is recovered by replica calculations for the Laplacian matrix) is reproduced exactly in the limit of infinite size of the blocks, or d→∞, which clarifies the physical meaning of space dimension in these models. We feel that the approximate results for d=3 provided by our method may have many potential applications in the future, from the vibrational spectrum of glasses and elastic networks to wave localization, disordered conductors, random resistor networks, and random walks.
  • ItemOpen AccessPublished version Peer-reviewed
    Continuous synthesis of hollow silver-palladium nanoparticles for catalytic applications.
    (Royal Society of Chemistry (RSC), 2018-09-03) Wu, Ke-Jun; Gao, Yunhu; Torrente-Murciano, Laura; Wu, Ke-Jun [0000-0001-8658-5449]; Gao, Yunhu [0000-0001-8483-7892]; Torrente-Murciano, Laura [0000-0002-7938-2587]
    Hollow bimetallic nanoparticles exhibit unique surface plasmonic properties, enhanced catalytic activities and high photo-thermal conversion efficiencies amongst other properties, however, their research and further deployment are currently limited by their complicated multi-step syntheses. This paper presents a novel approach for their continuous synthesis with controllable and tuneable sizes and compositions. This robust manufacturing tool, consisting of coiled flow inverter (CFI) reactors connected in series, allows for the first time the temporal and spatial separation of the initial formation of silver seeds and their subsequent galvanic displacement reaction in the presence of a palladium precursor, leading to the full control of both steps separately. We have also demonstrated that coupling the galvanic replacement and co-reduction leads to a great kinetic enhancement of the system leading to a high yield process of hollow bimetallic nanoparticles, directly applicable to other metal combinations.
  • ItemOpen AccessAccepted version Peer-reviewed
    Efficient multiobjective optimization employing Gaussian processes, spectral sampling and a genetic algorithm
    (Springer Science and Business Media LLC, 2018) Bradford, E; Schweidtmann, AM; Lapkin, A; Bradford, E [0000-0002-0803-0576]; Schweidtmann, AM [0000-0001-8885-6847]; Lapkin, A [0000-0001-7621-0889]
    Many engineering problems require the optimization of expensive, black-box functions involving multiple conflicting criteria, such that commonly used methods like multiobjective genetic algorithms are inadequate. To tackle this problem several algorithms have been developed using surrogates. However, these often have disadvantages such as the requirement of a priori knowledge of the output functions or exponentially scaling computational cost with respect to the number of objectives. In this paper a new algorithm is proposed, TSEMO, which uses Gaussian processes as surrogates. The Gaussian processes are sampled using spectral sampling techniques to make use of Thompson sampling in conjunction with the hypervolume quality indicator and NSGA-II to choose a new evaluation point at each iteration. The reference point required for the hypervolume calculation is estimated within TSEMO. Further, a simple extension was proposed to carry out batch-sequential design. TSEMO was compared to ParEGO, an expected hypervolume implementation, and NSGA-II on 9 test problems with a budget of 150 function evaluations. Overall, TSEMO shows promising performance, while giving a simple algorithm without the requirement of a priori knowledge, reduced hypervolume calculations to approach linear scaling with respect to the number of objectives, the capacity to handle noise and lastly the ability for batch-sequential usage.
  • ItemOpen AccessAccepted version Peer-reviewed
    Glass-Transition Temperature of the β-Relaxation as the Major Predictive Parameter for Recrystallization of Neat Amorphous Drugs.
    (American Chemical Society (ACS), 2018-03-15) Kissi, Eric Ofosu; Grohganz, Holger; Löbmann, Korbinian; Ruggiero, Michael T; Zeitler, J Axel; Rades, Thomas; Kissi, Eric Ofosu [0000-0001-9301-9939]; Grohganz, Holger [0000-0002-0482-1397]; Ruggiero, Michael T [0000-0003-1848-2565]; Zeitler, J Axel [0000-0002-4958-0582]; Rades, Thomas [0000-0002-7521-6020]
    Recrystallization of amorphous drugs is currently limiting the simple approach to improve solubility and bioavailability of poorly water-soluble drugs by amorphization of a crystalline form of the drug. In view of this, molecular mobility, α-relaxation and β-relaxation processes with the associated transition temperatures Tgα and Tgβ, was investigated using dynamic mechanical analysis (DMA). The correlation between the transition temperatures and the onset of recrystallization for nine amorphous drugs, stored under dry conditions at a temperature of 296 K, was determined. From the results obtained, Tgα does not correlate with the onset of recrystallization under the experimental storage conditions. However, a clear correlation between Tgβ and the onset of recrystallization was observed. It is shown that at storage temperature below Tgβ, amorphous nifedipine retains its amorphous form. On the basis of the correlation, an empirical correlation is proposed for predicting the onset of recrystallization for drugs stored at 0% RH and 296 K.