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- Baatallah, N., et al.
(author)
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Pharmacological chaperones improve intra-domain stability and inter-domain assembly via distinct binding sites to rescue misfolded CFTR
- 2021
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In: Cellular and Molecular Life Sciences (CMLS). - : Springer Nature. - 1420-682X .- 1420-9071. ; 78:23, s. 7813-7829
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Journal article (peer-reviewed)abstract
- Protein misfolding is involved in a large number of diseases, among which cystic fibrosis. Complex intra- and inter-domain folding defects associated with mutations in the cystic fibrosis transmembrane regulator (CFTR) gene, among which p.Phe508del (F508del), have recently become a therapeutical target. Clinically approved correctors such as VX-809, VX-661, and VX-445, rescue mutant protein. However, their binding sites and mechanisms of action are still incompletely understood. Blind docking onto the 3D structures of both the first membrane-spanning domain (MSD1) and the first nucleotide-binding domain (NBD1), followed by molecular dynamics simulations, revealed the presence of two potential VX-809 corrector binding sites which, when mutated, abrogated rescue. Network of amino acids in the lasso helix 2 and the intracellular loops ICL1 and ICL4 allosterically coupled MSD1 and NBD1. Corrector VX-445 also occupied two potential binding sites on MSD1 and NBD1, the latter being shared with VX-809. Binding of both correctors on MSD1 enhanced the allostery between MSD1 and NBD1, hence the increased efficacy of the corrector combination. These correctors improve both intra-domain folding by stabilizing fragile protein–lipid interfaces and inter-domain assembly via distant allosteric couplings. These results provide novel mechanistic insights into the rescue of misfolded proteins by small molecules.
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- Heindel, Jerrold J., et al.
(author)
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Obesity II : Establishing causal links between chemical exposures and obesity
- 2022
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In: Biochemical Pharmacology. - : Elsevier. - 0006-2952 .- 1356-1839 .- 1873-2968. ; 199
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Research review (peer-reviewed)abstract
- Obesity is a multifactorial disease with both genetic and environmental components. The prevailing view is that obesity results from an imbalance between energy intake and expenditure caused by overeating and insufficient exercise. We describe another environmental element that can alter the balance between energy intake and energy expenditure: obesogens. Obesogens are a subset of environmental chemicals that act as endocrine disruptors affecting metabolic endpoints. The obesogen hypothesis posits that exposure to endocrine disruptors and other chemicals can alter the development and function of the adipose tissue, liver, pancreas, gastrointestinal tract, and brain, thus changing the set point for control of metabolism. Obesogens can determine how much food is needed to maintain homeostasis and thereby increase the susceptibility to obesity. The most sensitive time for obesogen action is in utero and early childhood, in part via epigenetic programming that can be transmitted to future generations. This review explores the evidence supporting the obesogen hypothesis and highlights knowledge gaps that have prevented widespread acceptance as a contributor to the obesity pandemic. Critically, the obesogen hypothesis changes the narrative from curing obesity to preventing obesity.
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- Kangas, Tuomas, et al.
(author)
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The morphology of the ejecta of SN 1987A at 31 yr from 1150 to 10 000 angstrom
- 2022
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In: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 511:2, s. 2977-2993
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Journal article (peer-reviewed)abstract
- We present spectroscopy of the ejecta of SN 1987A in 2017 and 2018 from the Hubble Space Telescope and the Very Large Telescope, covering the wavelength range between 1150 and 10000 angstrom. At 31 yr, this is the first epoch with coverage over the ultraviolet-to-near-infrared range since 1995. We create velocity maps of the ejecta in the H alpha, Mg II lambda lambda 2796, 2804 and [OI] lambda lambda 6302, 6366 (vacuum) emission lines and study their morphology. All three lines have a similar morphology, but Mg II is blueshifted by similar to 1000 km s(-1) relative to the others and stronger in the north-west. We also study the evolution of the line fluxes, finding a brightening by a factor of similar to 9 since 1999 in Mg II, while the other line fluxes are similar in 1999 and 2018. We discuss implications for the power sources of emission lines at late times: thermal excitation due to heating by the X-rays from the ejecta-ring interaction is found to dominate the ultraviolet Mg II lines, while the infrared Mg II doublet is powered mainly by Ly alpha fluorescence. The X-ray deposition is calculated based on merger models of SN 1987A. Far-ultraviolet emission lines of H-2 are not detected. Finally, we examine the combined spectrum of recently discovered hotspots outside the equatorial ring. Their unresolved Balmer emission lines close to zero velocity are consistent with the interaction of fast ejecta and a clumpy, slowly moving outflow. A clump of emission in this spectrum, south of the equatorial ring at similar to 1500 km s(-1), is likely associated with the reverse shock.
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- Preiss, L., et al.
(author)
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Bone healing, tissue effects and biomechanical fixation of ‘smooth’ ceramic-coated zirconia-based dental implants : An in vivo study in sheep
- 2024
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In: Open Ceramics. - : Elsevier B.V.. - 2666-5395. ; 17
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Journal article (peer-reviewed)abstract
- In this study, the effect of coating a zirconia-based ceramic oral implant with a material of the same composition to build a relatively smooth surface with three different porosity features was evaluated in vivo, at 4 and 8 weeks after implantation in sheep femoral condyles. The results showed that at 4 weeks, the three coated zirconia-based implants with smoother surface topographies behaved similarly and promoted faster bone healing compared to the results obtained in the same zirconia- or titanium-based implants, but with rougher sandblasted and acid-etched surfaces. In addition, higher pull-out strengths were estimated in the coated-ceramic sample compared to titanium sandblasted and etched one. The present work showed that zirconia coatings with smoother surfaces than those conventionally used in the market improved the early phase of bone healing, paving the way for shorter treatment times and improved patient outcomes.
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