| 1. |
- Malhotra, Rajeev, et al.
(author)
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HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype
- 2019
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 51:11, s. 1580-
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Journal article (peer-reviewed)abstract
- Aortic calcification is an important independent predictor of future cardiovascular events. We performed a genome-wide association meta-analysis to determine SNPs associated with the extent of abdominal aortic calcification (n = 9,417) or descending thoracic aortic calcification (n = 8,422). Two genetic loci, HDAC9 and RAP1GAP, were associated with abdominal aortic calcification at a genome-wide level (P < 5.0 × 10−8). No SNPs were associated with thoracic aortic calcification at the genome-wide threshold. Increased expression of HDAC9 in human aortic smooth muscle cells promoted calcification and reduced contractility, while inhibition of HDAC9 in human aortic smooth muscle cells inhibited calcification and enhanced cell contractility. In matrix Gla protein–deficient mice, a model of human vascular calcification, mice lacking HDAC9 had a 40% reduction in aortic calcification and improved survival. This translational genomic study identifies the first genetic risk locus associated with calcification of the abdominal aorta and describes a previously unknown role for HDAC9 in the development of vascular calcification.
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| 2. |
- Cao, C., et al.
(author)
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Giant two-phonon Raman scattering from nanoscale NbC precipitates in Nb
- 2015
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In: Physical Review B Condensed Matter. - : American Physical Society. - 0163-1829 .- 1095-3795. ; 91:9
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Journal article (peer-reviewed)abstract
- High purity niobium (Nb), subjected to the processing methods used in the fabrication of superconducting RF cavities, displays micron-sized surface patches containing excess carbon. High-resolution transmission electron microscopy and electron energy-loss spectroscopy measurements are presented which reveal the presence of nanoscale NbC coherent precipitates in such regions. Raman backscatter spectroscopy on similar surface regions exhibit spectra consistent with the literature results on bulk NbC but with significantly enhanced two-phonon scattering. The unprecedented strength and sharpness of the two-phonon signal has prompted a theoretical analysis, using density functional theory (DFT), of phonon modes in NbC for two different interface models of the coherent precipitate. One model leads to overall compressive strain and a comparison to ab-initio calculations of phonon dispersion curves under uniform compression of the NbC shows that the measured two-phonon peaks are linked directly to phonon anomalies arising from strong electron-phonon interaction. Another model of the extended interface between Nb and NbC, studied by DFT, gives insight into the frequency shifts of the acoustic and optical mode density of states measured by first order Raman. The exact origin of the stronger two-phonon response is not known at present but it suggests the possibility of enhanced electron-phonon coupling in transition metal carbides under strain found either in the bulk NbC inclusions or at their interfaces with Nb metal. Preliminary tunneling studies using a point contact method show some energy gaps larger than expected for bulk NbC.
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| 3. |
- Hindle, Allyson G., et al.
(author)
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Low guanylyl cyclase activity in Weddell seals : implications for peripheral vasoconstriction and perfusion of the brain during diving
- 2019
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In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology. - : AMER PHYSIOLOGICAL SOC. - 0363-6119 .- 1522-1490. ; 316:6, s. R704-R715
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Journal article (peer-reviewed)abstract
- Nitric oxide (NO) is a potent vasodilator, which improves perfusion and oxygen delivery during tissue hypoxia in terrestrial animals. The vertebrate dive response involves vasoconstriction in select tissues. which persists despite profound hypoxia. Using tissues collected from Weddell seals at necropsy, we investigated whether vasoconstriction is aided by downregulation of local hypoxia signaling mechanisms. We focused on NO-soluble guanylyl cyclasc (GC)-cGMP signaling, a well-known vasodilatory transduction pathway. Seals have a lower GC protein abundance. activity, and capacity to respond to NO stimulation than do terrestrial mammals. In seal lung homogenates, GC produced less cGMP (20.1 +/- 3.7 pmol.mg protein(-1).min(-1)) than the lungs of dogs (-80 +/- 144 pmol.mg protein(-1).min(-1) less than seals), sheep (-472 +/- 96), rats (-664 +/- 104) or mice ( -1,160 +/- 104, P < 0.0001). Amino acid sequences of the GC enzyme alpha-subunits differed between seals and terrestrial mammals, potentially affecting their structure and function. Vasoconstriction in diving Weddell seals is not consistent across tissues; perfusion is maintained in the brain and heart but decreased in other organs such as the kidney. A NO donor increased median GC activity 49.5-fold in the seal brain but only 27.4-fold in the kidney. consistent with the priority of cerebral perfusion during diving. Nos3 expression was high in the seal brain, which could improve NO production and vasodilatory potential. Conversely, Pde5a expression was high in the seal renal artery, which may increase cGMP breakdown and vasoconstriction in the kidney. Taken together, the results of this study suggest that alterations in the NO-cGMP pathway facilitate the diving response.
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| 4. |
- Noh, Hyun Ji, et al.
(author)
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The Antarctic Weddell seal genome reveals evidence of selection on cardiovascular phenotype and lipid handling
- 2022
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In: Communications Biology. - : Springer Nature. - 2399-3642. ; 5:1
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Journal article (peer-reviewed)abstract
- The Weddell seal (Leptonychotes weddellii) thrives in its extreme Antarctic environment. We generated the Weddell seal genome assembly and a high-quality annotation to investigate genome-wide evolutionary pressures that underlie its phenotype and to study genes implicated in hypoxia tolerance and a lipid-based metabolism. Genome-wide analyses included gene family expansion/contraction, positive selection, and diverged sequence (acceleration) compared to other placental mammals, identifying selection in coding and non-coding sequence in five pathways that may shape cardiovascular phenotype. Lipid metabolism as well as hypoxia genes contained more accelerated regions in the Weddell seal compared to genomic background. Top-significant genes were SUMO2 and EP300; both regulate hypoxia inducible factor signaling. Liver expression of four genes with the strongest acceleration signals differ between Weddell seals and a terrestrial mammal, sheep. We also report a high-density lipoprotein-like particle in Weddell seal serum not present in other mammals, including the shallow-diving harbor seal. The Antarctic Weddell inhabits one of the most extreme environments on Earth. Comparative genomics with close relatives reveals the specific genetic adaptations for cardiovascular and fat metabolism that enable it to thrive.
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