| 1. |
- Smati, S., et al.
(författare)
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Integrative study of diet-induced mouse models of NAFLD identifies PPARα as a sexually dimorphic drug target
- 2022
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Ingår i: Gut. - : BMJ Publishing Group. - 0017-5749 .- 1468-3288. ; 71:4, s. 807-821
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Tidskriftsartikel (refereegranskat)abstract
- We evaluated the influence of sex on the pathophysiology of non-alcoholic fatty liver disease (NAFLD). We investigated diet-induced phenotypic responses to define sex-specific regulation between healthy liver and NAFLD to identify influential pathways in different preclinical murine models and their relevance in humans. Different models of diet-induced NAFLD (high-fat diet, choline-deficient high-fat diet, Western diet or Western diet supplemented with fructose and glucose in drinking water) were compared with a control diet in male and female mice. We performed metabolic phenotyping, including plasma biochemistry and liver histology, untargeted large-scale approaches (liver metabolome, lipidome and transcriptome), gene expression profiling and network analysis to identify sex-specific pathways in the mouse liver. The different diets induced sex-specific responses that illustrated an increased susceptibility to NAFLD in male mice. The most severe lipid accumulation and inflammation/fibrosis occurred in males receiving the high-fat diet and Western diet, respectively. Sex-biased hepatic gene signatures were identified for these different dietary challenges. The peroxisome proliferator-activated receptor α (PPARα) co-expression network was identified as sexually dimorphic, and in vivo experiments in mice demonstrated that hepatocyte PPARα determines a sex-specific response to fasting and treatment with pemafibrate, a selective PPARα agonist. Liver molecular signatures in humans also provided evidence of sexually dimorphic gene expression profiles and the sex-specific co-expression network for PPARα. These findings underscore the sex specificity of NAFLD pathophysiology in preclinical studies and identify PPARα as a pivotal, sexually dimorphic, pharmacological target. NCT02390232.
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| 2. |
- Ahmad, Amais, et al.
(författare)
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IMI – Oral biopharmaceutics tools project – Evaluation of bottom-up PBPK prediction success part 4 : Prediction accuracy and software comparisons with improved data and modelling strategies
- 2020
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier BV. - 0939-6411 .- 1873-3441. ; 156, s. 50-63
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Tidskriftsartikel (refereegranskat)abstract
- Oral drug absorption is a complex process depending on many factors, including the physicochemical properties of the drug, formulation characteristics and their interplay with gastrointestinal physiology and biology. Physiological-based pharmacokinetic (PBPK) models integrate all available information on gastro-intestinal system with drug and formulation data to predict oral drug absorption. The latter together with in vitro-in vivo extrapolation and other preclinical data on drug disposition can be used to predict plasma concentration-time profiles in silico. Despite recent successes of PBPK in many areas of drug development, an improvement in their utility for evaluating oral absorption is much needed. Current status of predictive performance, within the confinement of commonly available in vitro data on drugs and formulations alongside systems information, were tested using 3 PBPK software packages (GI-Sim (ver.4.1), Simcyp® Simulator (ver.15.0.86.0), and GastroPlusTM (ver.9.0.00xx)). This was part of the Innovative Medicines Initiative (IMI) Oral Biopharmaceutics Tools (OrBiTo) project.Fifty eight active pharmaceutical ingredients (APIs) were qualified from the OrBiTo database to be part of the investigation based on a priori set criteria on availability of minimum necessary information to allow modelling exercise. The set entailed over 200 human clinical studies with over 700 study arms. These were simulated using input parameters which had been harmonised by a panel of experts across different software packages prior to conduct of any simulation. Overall prediction performance and software packages comparison were evaluated based on performance indicators (Fold error (FE), Average fold error (AFE) and absolute average fold error (AAFE)) of pharmacokinetic (PK) parameters.On average, PK parameters (Area Under the Concentration-time curve (AUC0-tlast), Maximal concentration (Cmax), half-life (t1/2)) were predicted with AFE values between 1.11 and 1.97. Variability in FEs of these PK parameters was relatively high with AAFE values ranging from 2.08 to 2.74. Around half of the simulations were within the 2-fold error for AUC0-tlast and around 90% of the simulations were within 10-fold error for AUC0-tlast. Oral bioavailability (Foral) predictions, which were limited to 19 APIs having intravenous (i.v.) human data, showed AFE and AAFE of values 1.37 and 1.75 respectively. Across different APIs, AFE of AUC0-tlast predictions were between 0.22 and 22.76 with 70% of the APIs showing an AFE > 1. When compared across different formulations and routes of administration, AUC0-tlast for oral controlled release and i.v. administration were better predicted than that for oral immediate release formulations. Average predictive performance did not clearly differ between software packages but some APIs showed a high level of variability in predictive performance across different software packages. This variability could be related to several factors such as compound specific properties, the quality and availability of information, and errors in scaling from in vitro and preclinical in vivo data to human in vivo behaviour which will be explored further. Results were compared with previous similar exercise when the input data selection was carried by the modeller rather than a panel of experts on each in vitro test. Overall, average predictive performance was increased as reflected in smaller AAFE value of 2.8 as compared to AAFE value of 3.8 in case of previous exercise.
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| 3. |
- Chauvat, Guillaume, et al.
(författare)
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Global linear analysis of a jet in cross-flow at low velocity ratios
- 2020
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Ingår i: Journal of Fluid Mechanics. - : CAMBRIDGE UNIV PRESS. - 0022-1120 .- 1469-7645. ; 889
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Tidskriftsartikel (refereegranskat)abstract
- The stability of the jet in cross-flow is investigated using a complete set-up including the flow inside the pipe. First, direct simulations were performed to find the critical velocity ratio as a function of the Reynolds number, keeping the boundary-layer displacement thickness fixed. At all Reynolds numbers investigated, there exists a steady regime at low velocity ratios. As the velocity ratio is increased, a bifurcation to a limit cycle composed of hairpin vortices is observed. The critical bulk velocity ratio is found at approximately for the Reynolds number , above which a global mode of the system becomes unstable. An impulse response analysis was performed and characteristics of the generated wave packets were analysed, which confirmed results of our global mode analysis. In order to study the sensitivity of this flow, we performed transient growth computations and also computed the optimal periodic forcing and its response. Even well below this stability limit, at , large transient growth ( in energy amplification) is possible and the resolvent norm of the linearized Navier-Stokes operator peaks above . This is accompanied with an extreme sensitivity of the spectrum to numerical details, making the computation of a few tens of eigenvalues close to the limit of what can be achieved with double precision arithmetic. We demonstrate that including the meshing of the jet pipe in the simulations does not change qualitatively the dynamics of the flow when compared to the simple Dirichlet boundary condition representing the jet velocity profile. This is in agreement with the recent experimental results of Klotz et al. (J. Fluid Mech., vol. 863, 2019, pp. 386-406) and in contrast to previous studies of Cambonie & Aider (Phys. Fluids, vol. 26, 2014, 084101). Our simulations also show that a small amount of noise at subcritical velocity ratios may trigger the shedding of hairpin vortices.
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| 4. |
- Chauvat, Guillaume, 1991-
(författare)
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Receptivity, Stability and Sensitivity analysis of two- and three-dimensional flows
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This work deals with various aspects of boundary-layer stability. Modal and non-modal approaches are first used in the study of the global stability of a jet in crossflow. This flow case presents a global instability in some regimes which results from a Hopf bifurcation from a steady wake to a limit cycle consisting of a shedding of hairpin vortices. The effects of non-normality are studied in relation with transient growth and numerical accuracy. It is shown that the equations must be solved to a very high accuracy in order to properly capture the spectrum and that the computational domain must be very long due to the elongated core of the instability. Non-modal techniques do not suffer from such issues. The so-called acoustic receptivity of a flat plate with a leading-edge is analysed using a global modes approach. This leads to a spatio-temporal analysis in which the modes must be corrected for the imaginary part of the eigenvalues. This correction involves the Parabolised Stability Equations (PSE). This work confirms results previously obtained through different methods. The stability of two- and three-dimensional boundary-layer flows in the presence of surface irregularities such as steps, gaps or humps is also studied using Direct Numerical Simulation (DNS). It is found that all the surface irregularities have a destabilising effect on stability of two-dimensional boundary layers, with the rectangular hump case being the most dangerous one. In the case of three-dimensional boundary layers the effects are more complex. Our results accurately reproduce the steady flows, caused by small forward-facing steps, from an experimental setup, and the interaction of saturated crossflow vortices with unsteady noise is discussed. This work also describes a new method related to modal decomposition of compressible flows with shocks. Traditional linear techniques such as the Proper Orthogonal Decomposition (POD) struggle to capture strong nonlinear phenomena such as shock motion. The proposed shock-fitting approach tackles this issue by interpolating data onto a grid following the discontinuities. This requires detecting and parametrising the shocks, then mapping the original flow fields onto a reference mesh. A method to generate this mapping in two-dimensional domains is presented. Then the method is applied to two two-dimensional cases in ascending complexity. In addition to faster decay of the singular values, the modes obtained are cleaner and devoid of oscillations around the shocks.
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| 5. |
- Hammond, Oliver S., et al.
(författare)
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Small-Angle Neutron Scattering Insights into 2-Ethylhexyl Laurate : A Remarkable Bioester
- 2024
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Ingår i: ACS Sustainable Chemistry and Engineering. - : American Chemical Society (ACS). - 2168-0485. ; 12:5, s. 1816-1821
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Tidskriftsartikel (refereegranskat)abstract
- Commercial (protiated) samples of the "green" and biodegradable bioester 2-ethylhexyl laurate (2-EHL) were mixed with D-2-EHL synthesized by hydrothermal deuteration, with the mixtures demonstrating bulk structuring in small-angle neutron scattering measurements. Analysis in a polymer scattering framework yielded a radius of gyration (R (g)) of 6.5 angstrom and a Kuhn length (alternatively described as the persistence length or average segment length) of 11.2 angstrom. Samples of 2-EHL dispersed in acetonitrile formed self-assembled structures exceeding the molecular dimensions of the 2-EHL, with a mean aggregation number (N-agg) of 3.5 +/- 0.2 molecules across the tested concentrations. We therefore present structural evidence that this ester can function as a nonionic (co)-surfactant. The available surfactant-like conformations appear to enable performance beyond the low calculated hydrophilic-lipophilic balance value of 2.9. Overall, our data offer an explanation for 2-EHL's interfacial adsorption properties via self-assembly, resulting in strong emolliency and lubricity for this sustainable ester-based bio-oil.
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| 6. |
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| 7. |
- Parra, Erick O. Burgos, et al.
(författare)
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Holographic Magnetic Imaging of Single-Layer Nanocontact Spin-Transfer Oscillators
- 2016
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Ingår i: IEEE transactions on magnetics. - : IEEE. - 0018-9464 .- 1941-0069. ; 52:7
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Tidskriftsartikel (refereegranskat)abstract
- Time-averaged images of the magnetization within single-layer spin-transfer oscillators have been obtained using the holography with extended reference by autocorrelation linear differential operator technique. Transport measurements on a Pd(5)-Cu(20)-Ni81Fe19(7)-Cu(2)-Pd(2) (in nanometers) stack with a 100 nm diameter nanocontact reveal the presence of vortex dynamics. Magnetic images of the device for injected current values of 24 and -24 mA suggest that a vortex has been ejected from the nanocontact and become pinned at the edge of the region that is visible through the Au mask.
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| 8. |
- Tocci, F., et al.
(författare)
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The Effect of 2-D Surface Irregularities on Laminar-Turbulent Transition : A Comparison of Numerical Methodologies
- 2021
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Ingår i: Notes on Numerical Fluid Mechanics and Multidisciplinary Design. - Cham : Springer Nature. ; , s. 246-256
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Konferensbidrag (refereegranskat)abstract
- The applicability of Local Stability Theory (LST), Parabolized Stability Equations (PSE) and the Adaptive Harmonic Linearized Navier-Stokes (AHLNS) approach is investigated in the presence of 2-D surface irregularities through comparison with Direct Numerical Simulations (DNS). Remarkably good agreement between DNS and AHLNS is obtained for the amplification curves of Tollmien-Schlichting (TS) waves in all the cases studied. The LST and PSE results exhibit differences which are discussed in relation to the local distortion of the boundary layer induced by the irregularities.
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