| 1. |
- Narangifard, A., et al.
(författare)
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Human skin barrier formation takes place via a cubic to lamellar lipid phase transition as analyzed by cryo-electron microscopy and EM-simulation
- 2018
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 366:2, s. 139-151
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Tidskriftsartikel (refereegranskat)abstract
- The skin's permeability barrier consists of stacked lipid sheets of splayed ceramides, cholesterol and free fatty acids, positioned intercellularly in the stratum corneum. We report here on the early stage of skin barrier formation taking place inside the tubuloreticular system in the secretory cells of the topmost viable epidermis and in the intercellular space between viable epidermis and stratum corneum. The barrier formation process was analysed in situ in its near-native state, using cryo-EM combined with molecular dynamics modeling and EM simulation. Stacks of lamellae appear towards the periphery of the tubuloreticular system and they are closely associated with granular regions. Only models based on a bicontinuous cubic phase organization proved compatible with the granular cryo-EM patterns. Only models based on a dehydrated lamellar phase organization agreed with the lamellar cryo-EM patterns. The data support that human skin barrier formation takes place via a cubic to lamellar lipid phase transition.
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| 2. |
- Eichenhofer, G., et al.
(författare)
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Industrial use of HiPIMS and the hiP-V hiPlus technology : A review by a manufacturer
- 2017
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Ingår i: Vakuum in Forschung und Praxis. - : Wiley-VCH Verlag. - 0947-076X .- 1522-2454. ; 29:2, s. 40-44
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Tidskriftsartikel (refereegranskat)abstract
- It has been demonstrated by several groups that HiPIMS is a state of the art tool for applying demanding coatings with superior film properties. The real industrial breakthrough for the HiPIMS-technology, has not yet happened. On the other hand, the up till now available HiPIMS-PS were mainly been up-scaled “prototypes”, far away from industrial work horses. With the hiP-V HiPIMS power system, a direct derivative of a robust power supply technology already in commercial use for public transportation systems, another milestone is set to make the HiPIMS technology go mainstream. HiPIMS is not a revolution that will make all other technologies obsolete, yet it is a very powerful complement. With a reliable, multi-functional power supply and with a rapid arc-handling, it could possibly be a start of a new era in thin film production. Just consider the possibility of etching and implantation to increase cleanliness and adhesion of the samples. Until now, most of the R&D work done in HiPIMS, has been dedicated to hard coatings and tool coatings. Here, HiPIMS is surely useful but not the expected technological breakthrough. For the future, the implementation of the new positive reverse pulse, the hiP-V hiPlus HiPIMS technology, is opening a whole new field of possible applications for i.e. nonconductive substrates where no bias can be applied. Glass and plastics can be processed with remarkable results in hardness, enhanced film properties and additionally, it is achieved at lower substrate temperatures. It has been a slow start for HiPIMS, but the future looks bright.
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| 3. |
- Lundborg, Magnus, et al.
(författare)
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Human skin barrier structure and function analyzed by cryo-EM and molecular dynamics simulation
- 2018
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Ingår i: Journal of Structural Biology. - : Academic Press. - 1047-8477 .- 1095-8657. ; 203:2, s. 149-161
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Tidskriftsartikel (refereegranskat)abstract
- In the present study we have analyzed the molecular structure and function of the human skin's permeability barrier using molecular dynamics simulation validated against cryo-electron microscopy data from near native skin. The skin's barrier capacity is located to an intercellular lipid structure embedding the cells of the superficial most layer of skin - the stratum corneum. According to the splayed bilayer model (Iwai et al., 2012) the lipid structure is organized as stacked bilayers of ceramides in a splayed chain conformation with cholesterol associated with the ceramide sphingoid moiety and free fatty acids associated with the ceramide fatty acid moiety. However, knowledge about the lipid structure's detailed molecular organization, and the roles of its different lipid constituents, remains circumstantial. Starting from a molecular dynamics model based on the splayed bilayer model, we have, by stepwise structural and compositional modifications, arrived at a thermodynamically stable molecular dynamics model expressing simulated electron microscopy patterns matching original cryo-electron microscopy patterns from skin extremely closely. Strikingly, the closer the individual molecular dynamics models' lipid composition was to that reported in human stratum corneum, the better was the match between the models' simulated electron microscopy patterns and the original cryo-electron microscopy patterns. Moreover, the closest-matching model's calculated water permeability and thermotropic behaviour were found compatible with that of human skin. The new model may facilitate more advanced physics-based skin permeability predictions of drugs and toxicants. The proposed procedure for molecular dynamics based analysis of cellular cryo-electron microscopy data might be applied to other biomolecular systems.
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| 4. |
- Lundborg, Magnus, et al.
(författare)
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Predicting drug permeability through skin using molecular dynamics simulation
- 2018
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Ingår i: Journal of Controlled Release. - : Elsevier. - 0168-3659 .- 1873-4995. ; 283, s. 269-279
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Tidskriftsartikel (refereegranskat)abstract
- Understanding and predicting permeability of compounds through skin is of interest for transdermal delivery of drugs and for toxicity predictions of chemicals. We show, using a new atomistic molecular dynamics model of the skin's barrier structure, itself validated against near-native cryo-electron microscopy data from human skin, that skin permeability to the reference compounds benzene, DMSO (dimethyl sulfoxide), ethanol, codeine, naproxen, nicotine, testosterone and water can be predicted. The permeability results were validated against skin permeability data in the literature. We have investigated the relation between skin barrier molecular organization and permeability using atomistic molecular dynamics simulation. Furthermore, it is shown that the calculated mechanism of action differs between the five skin penetration enhancers Azone, DMSO, oleic acid, stearic acid and water. The permeability enhancing effect of a given penetration enhancer depends on the permeating compound and on the concentration of penetration enhancer inside the skin's barrier structure. The presented method may open the door for computer based screening of the permeation of drugs and toxic compounds through skin.
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| 5. |
- Narangifard, Ali, et al.
(författare)
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Molecular Reorganization during the Formation of the Human Skin Barrier Studied In Situ
- 2021
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Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X .- 1523-1747. ; 141:5, s. 1243-1253
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Tidskriftsartikel (refereegranskat)abstract
- In vertebrates, skin upholds homeostasis by preventing body water loss. The skin's permeability barrier is located intercellularly in the stratum corneum and consists of stacked lipid lamellae composed of ceramides, cholesterol, and free fatty acids. We have combined cryo-electron microscopy with molecular dynamics modeling and electron microscopy simulation in our analysis of the lamellae's formation, a maturation process beginning in stratum granulosum and ending in stratum corneum. Previously, we have revealed the lipid lamellae's initial- and end-stage molecular organizations. In this study, we reveal two cryo-electron microscopy patterns representing intermediate stages in the lamellae's maturation process: a single-band pattern with 2.0-2.5 nm periodicity and a two-band pattern with 5.5-6.0 nm periodicity, which may be derived from lamellar lipid structures with 4.0-5.0 nm and 5.5-6.0 nm periodicity, respectively. On the basis of the analysis of the data now available on the four maturation stages identified, we can present a tentative molecular model for the complete skin barrier formation process.
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| 6. |
- Wennberg, Christian L., et al.
(författare)
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Direct-Space Corrections Enable Fast and Accurate Lorentz-Berthelot Combination Rule Lennard-Jones Lattice Summation
- 2015
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Ingår i: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 11:12, s. 5737-5746
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Tidskriftsartikel (refereegranskat)abstract
- Long-range lattice summation techniques such as the particle-mesh Ewald (PME) algorithm for electrostatics have been revolutionary to the precision and accuracy of molecular simulations in general. Despite the performance penalty associated with lattice summation electrostatics, few biomolecular simulations today are performed without it. There are increasingly strong arguments for moving in the same direction for Lennard-Jones (LJ) interactions, and by using geometric approximations of the combination rules in reciprocal space, we have been able to make a very high-performance implementation available in GROMACS. Here, we present a new way to correct for these approximations to achieve exact treatment of Lorentz-Berthelot combination rules within the cutoff, and only a very small approximation error remains outside the cutoff (a part that would be completely ignored without LJ-PME). This not only improves accuracy by almost an order of magnitude but also achieves absolute biomolecular simulation performance that is an order of magnitude faster than any other available lattice summation technique for LJ interactions. The implementation includes both CPU and GPU acceleration, and its combination with improved scaling LJ-PME simulations now provides performance close to the truncated potential methods in GROMACS but with much higher accuracy.
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| 7. |
- Wennberg, Christian L., 1986-
(författare)
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Exploring the Interactive Landscape of Lipid Bilayers
- 2014
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- One of the most important aspects for all life on this planet is theact to keep their cellular processes in a state where they do notreach equilibrium. One part in the upholding of this imbalanced stateis the barrier between the cells and their surroundings, created bythe cell membrane. In addition to experiments, the investigation ofprocesses occuring in the cell membrane can be performed by usingmolecular dynamics simulations. Through this method we can obtain anatomistic description of the dynamics associated with events that arenot accessible to experimental setups. Molecular dynamics relies onthe integration of Newton's equations of motion in order to sample therelevant parts of phase-space for the system, and therefore it isdependent on a correct description of the interactions between all thesimulated particles. In this thesis I first present an improved methodfor the calculation of long-range interactions in molecular dynamicssimulations, followed by a study of cholesterol's impact on thepermeation of small solutes across a lipid bilayer.The first paper presents a previously derived modification to theparticle-mesh Ewald method, which makes it possible to apply thisto long-range Lennard-Jones interactions. Old implementations of themethod have been haunted by an extreme performance degradation andhere I propose a solution to this problem by applying a modifiedinteraction potential. I further show that the historical treatmentof long-range interactions in simulations of lipid bilayers hasnon-negligible effects on their structural properties.In the second paper, this modification is improved such that the smallerrors introduced by the modified interaction potential becomenegligible. Furthermore, I demonstrate that I have also improved theimplementation of the method so that it now only incurs a performanceloss of roughly 15% compared to conventional simulations using theGromacs simulation package.The third paper presents a simulation study of cholesterol's effect onthe permeation of six different solutes across a variety of lipidbilayers. I analyze the effect of different head groups, tail lengths,and tail saturation by performing simulations of the solutes in fourdifferent bilayers, with cholesterol contents between 0% and50%. Analysis of the simulations shows that the impact of the surfacearea per lipid on the partitioning of the solute could be lower thanpreviously thought. Furthermore, a model with a laterallyinhomogeneous permeability in cholesterol-containing membranes isproposed, which could explain the large differences betweenpermeabilities from experiments and calculated partition coefficientsin simulations.
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| 8. |
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| 9. |
- Wennberg, Christian L., et al.
(författare)
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Large Influence of Cholesterol on Solute Partitioning into Lipid Membranes
- 2012
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 134:11, s. 5351-5361
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Tidskriftsartikel (refereegranskat)abstract
- Cholesterol plays an important role in maintaining the correct fluidity and rigidity of the plasma membrane of all animal cells, and hence, it is present in concentrations ranging from 20 to 50 mol %. Whereas the effect of cholesterol on such mechanical properties has been studied exhaustively over the last decades, the structural basis for cholesterol effects on membrane permeability is still unclear. Here we apply systematic molecular dynamics simulations to study the partitioning of solutes between water and membranes. We derive potentials of mean force for six different solutes permeating across 20 different lipid membranes containing one out of four types of phospholipids plus a cholesterol content varying from 0 to 50 mol %. Surprisingly, cholesterol decreases solute partitioning into the lipid tail region of the membranes much more strongly than expected from experiments on macroscopic membranes, suggesting that a laterally inhomogeneous cholesterol concentration and permeability may be required to explain experimental findings. The simulations indicate that the cost of breaking van der Waals interactions between the lipid tails of cholesterol-containing membranes account for the reduced partitioning rather than the surface area per phospholipid, which has been frequently suggested as a determinant for solute partitioning. The simulations further show that the partitioning is more sensitive to cholesterol (i) for larger solutes, (ii) in membranes with saturated as compared to membranes with unsaturated lipid tails, and (iii) in membranes with smaller lipid head groups.
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| 10. |
- Wennberg, Christian L., et al.
(författare)
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Lennard-Jones Lattice Summation in Bilayer Simulations Has Critical Effects on Surface Tension and Lipid Properties
- 2013
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Ingår i: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 9:8, s. 3527-3537
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Tidskriftsartikel (refereegranskat)abstract
- The accuracy of electrostatic interactions in molecular dynamics advanced tremendously with the introduction of particle-mesh Ewald (PME) summation almost 20 years ago. Lattice summation electrostatics is now the de facto standard for most types of biomolecular simulations, and in particular, for lipid bilayers, it has been a critical improvement due to the large charges typically present in zwitterionic lipid headgroups. In contrast, Lennard-Jones interactions have continued to be handled with increasingly longer cutoffs, partly because few alternatives have been available despite significant difficulties in tuning cutoffs and parameters to reproduce lipid properties. Here, we present a new Lennard-Jones PME implementation applied to lipid bilayers. We confirm that long-range contributions are well approximated by dispersion corrections in simple systems such as pentadecane (which makes parameters transferable), but for inhomogeneous and anisotropic systems such as lipid bilayers there are large effects on surface tension, resulting in up to 5.5% deviations in area per lipid and order parameters-far larger than many differences for which reparameterization has been attempted. We further propose an approximation for combination rules in reciprocal space that significantly reduces the computational cost of Lennard-Jones PME and makes accurate treatment of all nonbonded interactions competitive with simulations employing long cutoffs. These results could potentially have broad impact on important applications such as membrane proteins and free energy calculations.
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