| 1. |
- Mishra, A., et al.
(författare)
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Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
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Tidskriftsartikel (refereegranskat)abstract
- Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
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| 2. |
- Wiessner, M., et al.
(författare)
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Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia
- 2021
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 144:5, s. 1422-1434
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Tidskriftsartikel (refereegranskat)abstract
- Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays. © 2021 The Author(s).
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| 3. |
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| 4. |
- Gupta, G., et al.
(författare)
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Exploiting Mass Spectrometry to Unlock the Mechanism of Nanoparticle-Induced Inflammasome Activation
- 2023
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Ingår i: Acs Nano. - : AMER CHEMICAL SOC. - 1936-0851 .- 1936-086X. ; 17:17, s. 17451-17467
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Tidskriftsartikel (refereegranskat)abstract
- Nanoparticles (NPs) elicit sterile inflammation, but the underlying signaling pathways are poorly understood. Here, we report that human monocytes are particularly vulnerable to amorphous silica NPs, as evidenced by single-cell-based analysis of peripheral blood mononuclear cells using cytometry by time-of-flight (CyToF), while silane modification of the NPs mitigated their toxicity. Using human THP-1 cells as a model, we observed cellular internalization of silica NPs by nanoscale secondary ion mass spectrometry (nanoSIMS) and this was confirmed by transmission electron microscopy. Lipid droplet accumulation was also noted in the exposed cells. Furthermore, time-of-flight secondary ion mass spectrometry (ToF-SIMS) revealed specific changes in plasma membrane lipids, including phosphatidylcholine (PC) in silica NP-exposed cells, and subsequent studies suggested that lysophosphatidylcholine (LPC) acts as a cell autonomous signal for inflammasome activation in the absence of priming with a microbial ligand. Moreover, we found that silica NPs elicited NLRP3 inflammasome activation in monocytes, whereas cell death transpired through a non-apoptotic, lipid peroxidation-dependent mechanism. Together, these data further our understanding of the mechanism of sterile inflammation.
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| 5. |
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| 6. |
- Bordes, Romain, 1981, et al.
(författare)
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Adsorption of Dianionic Surfactants Based on Amino Acids at Different Surfaces Studied by QCM-D and SPR
- 2010
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Ingår i: Langmuir. - : American Chemical Society (ACS). - 1520-5827 .- 0743-7463. ; 26:13, s. 10935-10942
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Tidskriftsartikel (refereegranskat)abstract
- The adsorption of three dicarboxylic amino acid-based surfactants, disodium N-lauroylaminomalonate, disodium N-lauroylaspartate, and disodium N-lauroylglutamate, has been studied by surface plasmon resonance (SPR) and the quartz crystal microbalance with dissipation monitoring (QCM-D). These surfactants have high cmc values, which means that the unimer concentration is high at the plateau value of adsorption. This gives rise to a considerable "bulk effect", which must be deducted from the observed value in order to obtain the true value of the adsorbed amount. In this article, we show how this can be done for the QCM-D technique. Adsorption is studied on silica, gold, gold hydrophobized by a self-assembled layer of an alkane thiol, and hydroxyapatite. Adsorption on hydroxyapatite differs very much among the three surfactants, with the aspartate derivative giving the strongest and the glutamate giving the weakest adsorption. This difference is explained as the difference in ability of the dicarboxylic amphiphiles to chelate calcium in the crystal lattice.
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| 7. |
- Bordes, Romain, 1981, et al.
(författare)
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Counterion Specificity of Surfactants Based on Dicarboxylic Amino Scids
- 2009
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Ingår i: Journal of Colloid and Interface Science. - : Elsevier BV. - 1095-7103 .- 0021-9797. ; 338:2, s. 529-536
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Tidskriftsartikel (refereegranskat)abstract
- The behavior in solution of a series of amino acid-based surfactants having two carboxyl groups separated by a spacer of one, two, or three carbon atoms has been investigated. All three surfactants precipitated on addition of acid, but the aspartate surfactant (with a two-carbon spacer) was considerably more resistant to precipitation than the aminomalonate surfactant (one-carbon spacer) and the glutamate surfactant (three-carbon spacer). The interactions with the monovalent counterions lithium, sodium, and potassium were investigated by conductivity. It was found that lithium ions bound the strongest and potassium ions the weakest to the surfactant micelles. These results were interpreted using the hard and soft acid-base theory. Comparing the three surfactants with respect to binding of one specific counterion, sodium, showed that the aminomalonate surfactant, which has the shortest spacer, bound sodium ions the strongest and the glutamate surfactant, which has the longest spacer, had the lowest affinity for the counterion. Also that could be explained by the hard and soft acid-base concept. The glutamate surfactant was found to be considerably more resistant to calcium ions than the two other surfactants. This was attributed to this surfactant forming an intermolecular complex with the calcium ion at the air-water interface while the aminomalonate and the aspartate surfactants, with shorter distance between the carboxylate groups could form six- and seven-membered intramolecular calcium complexes.
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| 8. |
- Bordes, Romain, 1981, et al.
(författare)
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Role of an amide bond for self-assembly of surfactants
- 2010
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Ingår i: Langmuir. - : American Chemical Society (ACS). - 1520-5827 .- 0743-7463. ; 26:5, s. 3077-3083
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Tidskriftsartikel (refereegranskat)abstract
- Self-assembly in Solution and adsorption at the air-water interface and at Solid Surfaces were investigated for two amino-acid-based surfactants with conductimetry, NMR, tensiometry, quartz crystal microbalance with monitoring or the dissipation (QCM-D), and surface plasmon resonance (SPR). The surfactants studied were sodium N-lauroylglycinate and sodium N-lauroylsarcosinate, differing only in a methyl group on the amide nitrogen for the sarcosinate. Thus, the glycinate but not the surfactant is capable of forming intermolecular hydrogen bonds via the amide group. It was found that the amide bond, N-methylated or not, gave a substantial contribution to the hydrophilicity of the amphiphile. The ability to form intermolecular hydrogen bonds led to tighter packing at the air-water interface and ill a hydrophobic surface. It also increased the tendency for precipitation as all acid-soap pair oil addition of acid. Adsorption of the surfactants at a gold surface Was also investigated and gave unexpected results. The sarcosine-based surfactant seemed to give bilayer adsorption, while the glycine derivative adsorbed as a monolayer.
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| 9. |
- Capron, Isabelle, et al.
(författare)
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Behavior of nanocelluloses at interfaces
- 2017
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Ingår i: Current Opinion in Colloid and Interface Science. - : Elsevier BV. - 1359-0294 .- 1879-0399. ; 29, s. 83-95
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Forskningsöversikt (refereegranskat)abstract
- Despite being non-surface active, nanocelluloses position efficiently at interfaces, already at very low concentration. This behavior has lately triggered a strong interest in the cellulose and colloids communities. This review reports the recent developments on the use of nanocelluloses at interfaces and highlights the fundamental principles governing the high efficiency observed in reinforcing the boundary between two phases. The use of nanocelluloses as emulsifier and emulsion stabilizer is first discussed, and the structural properties of nanocelluloses such as aspect ratio and surface properties are correlated with the high efficiency in forming colloidally-stable multiphase systems. Then, the behavior at the air/water interface is presented and the most recent advances are reviewed with focus on the surface free energy of nanocelluloses and their role in the interfacial self-assembly process.
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| 10. |
- Cheng, J., et al.
(författare)
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One-pot synthesis of porous gold nanoparticles by preparation of Ag/Au nanoparticles followed by dealloying
- 2013
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Ingår i: Colloids and Surfaces A: Physicochemical and Engineering Aspects. - : Elsevier BV. - 1873-4359 .- 0927-7757. ; 436, s. 823-829
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Tidskriftsartikel (refereegranskat)abstract
- Porous gold nanoparticles were obtained from nanoparticle alloys of gold and silver. The alloy nanoparticles were prepared by reducing the gold and silver precursors, HAuCl4 and AgNO3, respectively with NaBH4. The reduction was made in a microemulsion of water-in-oil type and the precursors were contained in the water droplets. The droplet size of the microemulsion was 25-30 nm and the size of the mixed nanoparticles was 5-7 nm. The position of the plasmon band in the absorption spectrum, as well as analysis by energy-dispersive X-ray spectroscopy linked to high resolution scanning transmission electron microscopy showed that the nanoparticles were true alloys, not of core-shell type. The mixed nanoparticles were subsequently dealloyed by treatment with nitric acid, which dissolved silver much more readily than gold.
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