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- Saliba-Gustafsson, P., et al.
(author)
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Subclinical atherosclerosis and its progression are modulated by PLIN2 through a feed-forward loop between LXR and autophagy
- 2019
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In: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 286:6, s. 660-675
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Journal article (peer-reviewed)abstract
- Background Hyperlipidaemia is a major risk factor for cardiovascular disease, and atherosclerosis is the underlying cause of both myocardial infarction and stroke. We have previously shown that the Pro251 variant of perilipin-2 reduces plasma triglycerides and may therefore be beneficial to reduce atherosclerosis development. Objective We sought to delineate putative beneficial effects of the Pro251 variant of perlipin-2 on subclinical atherosclerosis and the mechanism by which it acts. Methods A pan-European cohort of high-risk individuals where carotid intima-media thickness has been assessed was adopted. Human primary monocyte-derived macrophages were prepared from whole blood from individuals recruited by perilipin-2 genotype or from buffy coats from the Karolinska University hospital blood central. Results The Pro251 variant of perilipin-2 is associated with decreased intima-media thickness at baseline and over 30 months of follow-up. Using human primary monocyte-derived macrophages from carriers of the beneficial Pro251 variant, we show that this variant increases autophagy activity, cholesterol efflux and a controlled inflammatory response. Through extensive mechanistic studies, we demonstrate that increase in autophagy activity is accompanied with an increase in liver-X-receptor (LXR) activity and that LXR and autophagy reciprocally activate each other in a feed-forward loop, regulated by CYP27A1 and 27OH-cholesterol. Conclusions For the first time, we show that perilipin-2 affects susceptibility to human atherosclerosis through activation of autophagy and stimulation of cholesterol efflux. We demonstrate that perilipin-2 modulates levels of the LXR ligand 27OH-cholesterol and initiates a feed-forward loop where LXR and autophagy reciprocally activate each other; the mechanism by which perilipin-2 exerts its beneficial effects on subclinical atherosclerosis.
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| 2. |
- Rakopoulos, Vasileios, et al.
(author)
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First isomeric yield ratio measurements by direct ion counting and implications for the angular momentum of the primary fission fragments
- 2018
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In: Physical Review C. - : AMER PHYSICAL SOC. - 2469-9985 .- 2469-9993. ; 98:2
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Journal article (peer-reviewed)abstract
- We report the first experimental determination of independent isomeric yield ratios using direct ion counting with a Penning trap, which offered such a high resolution in mass that isomeric states could be separated. The measurements were performed at the Ion Guide Isotope Separator On-Line (IGISOL) facility at the University of Jyvaskyla. The isomer production ratios of Ge-81, Y-96,Y-97 Sn-128(,1)30, and Sb-129 in the 25-MeV proton-induced fission of U-na(t) and Th-232 were studied. Three isomeric pairs (Ge-81, Y-96, and Sb-129) were measured for the first time for the U-na(t)(p, f) reaction, while all the reported yield ratios for the Th-232(p, f) reaction were determined for the first time. The comparison of the experimentally determined isomeric yield ratios with data available in the literature shows a reasonable agreement, except for the case of Sn-130 for unspecified reasons. The obtained results were also compared with the GEF model, where good agreement can be noticed in most cases for both reactions. Serious discrepancies can only be observed for the cases of Y-96(,)97 for both reactions. Moreover, based on the isomeric yield ratios, the root-mean-square angular momenta (J(r)(ms)) of the fission fragments after scission were estimated using the TALYS code. The experimentally determined isomeric yield ratios, and consequently the deduced J(rms), for Sn-130 are significantly lower compared to Sn-128 for both fissioning systems. This can be attributed to the more spherical shape of the fragments that contribute to the formation of Sn-130, due to their proximity to the N = 82 shell closure. The values of J(rms) for Sb-129 are higher than Sn-128 for both reactions, despite the same neutron number of both nuclides (N = 78), indicating the odd-Z effect where fission fragments with odd-Z number tend to bear larger angular momentum than even-Z fragments. The isomer production ratio for the isotopes of Sn is more enhanced in the U-na(t)(p, f) reaction than in Th-232(p, f). The opposite is observed for Y-96 and Y-97. These discrepancies might be associated to different scission shapes of the fragments for the two fission reactions, indicating the impact that the different fission modes can have on the isomeric yield ratios.
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| 3. |
- Ribas, D., et al.
(author)
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Yeast as a tool to express sugar acid transporters with biotechnological interest
- 2017
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In: FEMS Yeast Research. - : Oxford University Press (OUP). - 1567-1356 .- 1567-1364. ; 17:2
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Journal article (peer-reviewed)abstract
- Sugar acids can be used as platform chemicals to generate primary building blocks of industrially relevant products. Microbial production of these organic compounds at high yields requires the engineering of the enzymatic machinery and the presence of plasma membrane transporters able to export them outside the cells. In this study, several yeast carboxylic acid transporters belonging to the Jen family were screened for the transport of biotechnologically relevant sugar acids, namely gluconic, saccharic, mucic, xylaric and xylonic acid, and functionally characterised in Saccharomyces cerevisiae. We show that Jen permeases are capable of transporting most of these sugar acids, although with different specificities. Saccharate is a substrate of the transporters ScJen1-S271Q and KlJen2, gluconate of CaJen2 and KlJen2, and xylarate and mucate of CaJen2. A molecular docking approach of these transporters identified the residues that play a major role in the substrate binding of these sugar acids, namely R188 (ScJen1), R122 (CaJen2) and R127 (KlJen2), all equivalent residues (TMS II). The identification of Jen members as sugar acid transporters can contribute to engineering efficient microbial cell factories with increased sugar acid production, as the ScJen1 is able to promote substrate efflux.
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