| 1. |
- Landegren, Nils, et al.
(author)
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A gene-centric approach to biomarker discovery identifies transglutaminase 1 as an epidermal autoantigen
- 2021
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 118:51
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Journal article (peer-reviewed)abstract
- Autoantigen discovery is a critical challenge for the understanding and diagnosis of autoimmune diseases. While autoantibody markers in current clinical use have been identified through studies focused on individual disorders, we postulated that a reverse approach starting with a putative autoantigen to explore multiple disorders might hold promise. We here targeted the epidermal protein transglutaminase 1 (TGM1) as a member of a protein family prone to autoimmune attack. By screening sera from patients with various acquired skin disorders, we identified seropositive subjects with the blistering mucocutaneous disease paraneoplastic pemphigus. Validation in further subjects confirmed TGM1 autoantibodies as a 55% sensitive and 100% specific marker for paraneoplastic pemphigus. This gene-centric approach leverages the wealth of data available for human genes and may prove generally applicable for biomarker discovery in autoimmune diseases.
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| 2. |
- Lundborg, Magnus, et al.
(author)
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Skin permeability prediction with MD simulation sampling spatial and alchemical reaction coordinates
- 2022
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In: Biophysical Journal. - : Biophysical Society. - 0006-3495 .- 1542-0086. ; 121:20, s. 3837-3849
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Journal article (peer-reviewed)abstract
- A molecular-level understanding of skin permeation may rationalize and streamline product development, and improve quality and control, of transdermal and topical drug delivery systems. It may also facilitate toxicity and safety assessment of cosmetics and skin care products. Here, we present new molecular dynamics simulation approaches that make it possible to efficiently sample the free energy and local diffusion coefficient across the skin’s barrier structure to predict skin permeability and the effects of chemical penetration enhancers. In particular, we introduce a new approach to use two-dimensional reaction coordinates in the accelerated weight histogram method, where we combine sampling along spatial coordinates with an alchemical perturbation virtual coordinate. We present predicted properties for 20 permeants, and demonstrate how our approach improves correlation with ex vivo/in vitro skin permeation data. For the compounds included in this study, the obtained log KPexp-calc mean square difference was 0.9 cm2 h−2.
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| 3. |
- Narangifard, Ali, et al.
(author)
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Molecular Reorganization during the Formation of the Human Skin Barrier Studied In Situ
- 2021
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In: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X .- 1523-1747. ; 141:5, s. 1243-1253
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Journal article (peer-reviewed)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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| 4. |
- Skröder, Helena, et al.
(author)
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Occupational exposure to whole-body vibrations and pregnancy complications : a nationwide cohort study in Sweden
- 2020
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In: Occupational and Environmental Medicine. - : BMJ Publishing Group Ltd. - 1351-0711 .- 1470-7926. ; 77:10, s. 691-698
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Journal article (peer-reviewed)abstract
- Objectives: Pregnancy complications are common contributors to perinatal mortality and morbidity. Still, the cause(s) of gestational hypertensive disorders and diabetes are largely unknown. Some occupational exposures have been inconsistently associated with pregnancy complications, but exposure to whole-body vibrations (WBV) has been largely overlooked even though it has been associated with adverse birth outcomes. Therefore, the aim was to assess whether occupational WBV exposure during pregnancy is associated with pregnancy complications in a nationwide, prospective cohort study.Methods: The Fetal Air Pollution Exposure cohort was formed by merging multiple Swedish, national registers containing information on occupation during pregnancy and diagnosis codes, and includes all working women who gave birth between 1994 and 2014 (n=1 091 044). WBV exposure was derived from a job-exposure matrix and was divided into categories (0, 0.1–0.2, 0.3–0.4 and ≥0.5 m/s2). ORs with 95% CIs were calculated using logistic regression adjusted for potential confounders.Results: Among women working full time (n=646 490), we found increased risks of all pregnancy complications in the highest exposure group (≥0.5 m/s2), compared with the lowest. The adjusted ORs were 1.76 (95% CI 1.41 to 2.20), 1.55 (95% CI 1.26 to 1.91) and 1.62 (95% CI 1.07 to 2.46) for preeclampsia, gestational hypertension and gestational diabetes, respectively, and were similar in all sensitivity analyses. There were no clear associations for part-time workers.Conclusions: The results suggest that women should not be exposed to WBV at/above the action limit value of 0.5 m/s2 (European directive) continuously through pregnancy. However, these results need further confirmation.
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| 5. |
- Wennberg, Christian, et al.
(author)
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Understanding Drug Skin Permeation Enhancers Using Molecular Dynamics Simulations
- 2023
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In: Journal of Chemical Information and Modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 63:15, s. 4900-4911
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Journal article (peer-reviewed)abstract
- Our skin constitutes an effective permeability barrier that protects the body from exogenous substances but concomitantly severely limits the number of pharmaceutical drugs that can be delivered transdermally. In topical formulation design, chemical permeation enhancers (PEs) are used to increase drug skin permeability. In vitro skin permeability experiments can measure net effects of PEs on transdermal drug transport, but they cannot explain the molecular mechanisms of interactions between drugs, permeation enhancers, and skin structure, which limits the possibility to rationally design better new drug formulations. Here we investigate the effect of the PEs water, lauric acid, geraniol, stearic acid, thymol, ethanol, oleic acid, and eucalyptol on the transdermal transport of metronidazole, caffeine, and naproxen. We use atomistic molecular dynamics (MD) simulations in combination with developed molecular models to calculate the free energy difference between 11 PE-containing formulations and the skin’s barrier structure. We then utilize the results to calculate the final concentration of PEs in skin. We obtain an RMSE of 0.58 log units for calculated partition coefficients from water into the barrier structure. We then use the modified PE-containing barrier structure to calculate the PEs’ permeability enhancement ratios (ERs) on transdermal metronidazole, caffeine, and naproxen transport and compare with the results obtained from in vitro experiments. We show that MD simulations are able to reproduce rankings based on ERs. However, strict quantitative correlation with experimental data needs further refinement, which is complicated by significant deviations between different measurements. Finally, we propose a model for how to use calculations of the potential of mean force of drugs across the skin’s barrier structure in a topical formulation design.
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