| 1. |
- Kanoni, Stavroula, et al.
(author)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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In: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Journal article (peer-reviewed)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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| 2. |
- Law, PJ, et al.
(author)
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Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia
- 2017
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8, s. 14175-
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Journal article (peer-reviewed)abstract
- Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P=5.04 × 10−13), 1q42.13 (rs41271473, P=1.06 × 10−10), 4q24 (rs71597109, P=1.37 × 10−10), 4q35.1 (rs57214277, P=3.69 × 10−8), 6p21.31 (rs3800461, P=1.97 × 10−8), 11q23.2 (rs61904987, P=2.64 × 10−11), 18q21.1 (rs1036935, P=3.27 × 10−8), 19p13.3 (rs7254272, P=4.67 × 10−8) and 22q13.33 (rs140522, P=2.70 × 10−9). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response.
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| 3. |
- Pink, Demi L., et al.
(author)
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Interplay of lipid and surfactant : Impact on nanoparticle structure
- 2021
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In: Journal of Colloid and Interface Science. - : Elsevier BV. - 0021-9797. ; 597, s. 278-288
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Journal article (peer-reviewed)abstract
- Liquid lipid nanoparticles (LLN) are oil-in-water nanoemulsions of great interest in the delivery of hydrophobic drug molecules. They consist of a surfactant shell and a liquid lipid core. The small size of LLNs makes them difficult to study, yet a detailed understanding of their internal structure is vital in developing stable drug delivery vehicles (DDVs). Here, we implement machine learning techniques alongside small angle neutron scattering experiments and molecular dynamics simulations to provide critical insight into the conformations and distributions of the lipid and surfactant throughout the LLN. We simulate the assembly of a single LLN composed of the lipid, triolein (GTO), and the surfactant, Brij O10. Our work shows that the addition of surfactant is pivotal in the formation of a disordered lipid core; the even coverage of Brij O10 across the LLN shields the GTO from water and so the lipids adopt conformations that reduce crystallisation. We demonstrate the superior ability of unsupervised artificial neural networks in characterising the internal structure of DDVs, when compared to more conventional geometric methods. We have identified, clustered, classified and averaged the dominant conformations of lipid and surfactant molecules within the LLN, providing a multi-scale picture of the internal structure of LLNs.
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| 4. |
- Pink, Demi L., et al.
(author)
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On the Structure of Solid Lipid Nanoparticles
- 2019
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In: Small. - : Wiley. - 1613-6810 .- 1613-6829.
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Journal article (peer-reviewed)abstract
- Solid lipid nanoparticles (SLNs) have a crystalline lipid core which is stabilized by interfacial surfactants. SLNs are considered favorable candidates for drug delivery vehicles since their ability to store and release organic molecules can be tailored through the identity of the lipids and surfactants used. When stored, polymorphic transitions in the core of drug-loaded SLNs lead to the premature release of drug molecules. Significant experimental studies have been conducted with the aim of investigating the physicochemical properties of SLNs, however, no molecular scale investigations have been reported on the behaviors that drive SLN formation and their polymorphic transitions. A combination of small angle neutron scattering and all-atom molecular dynamics simulations is therefore used to yield a detailed atomistic description of the internal structure of an SLN comprising triglyceride, tripalmitin, and the nonionic surfactant, Brij O10 (C18:1E10). The molecular scale mechanisms by which the surfactants stabilize the crystalline structure of the SLN lipid core are uncovered. By comparing these results to simulated liquid and solid aggregates of tripalmitin lipids, how the morphology of the lipids vary between these systems is demonstrated providing further insight into the mechanisms that control drug encapsulation and release from SLNs.
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| 5. |
- Ahmadi, Delaram, et al.
(author)
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Nanoscale Structure and Dynamics of Model Membrane Lipid Raft Systems, Studied by Neutron Scattering Methods
- 2022
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In: Frontiers in Physics. - : Frontiers Media SA. - 2296-424X. ; 10
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Journal article (peer-reviewed)abstract
- Quasi-elastic neutron scattering (QENS) and small angle neutron scattering (SANS), in combination with isotopic contrast variation, have been used to determine the structure and dynamics of three-component lipid membranes, in the form of vesicles, comprising an unsaturated [palmitoyl-oleoyl-phosphatidylcholine (POPC) or dioleoyl-phosphatidylcholine (DOPC)], a saturated phospholipid (dipalmitoyl-phosphatidylcholine (DPPC)), and cholesterol, as a function temperature and composition. SANS studies showed vesicle membranes composed of a 1:1:1 molar ratio of DPPC:DOPC:cholesterol and a 2:2:1 molar ratio of DPPC:POPC:cholesterol phase separated, forming lipid rafts of ∼18 and ∼7 nm diameter respectively, when decreasing temperature from 308 to 297 K. Phase separation was reversible upon increasing temperature. The larger rafts observed in systems containing DOPC are attributed to the greater mis-match in lipid alkyl chains between DOPC and DPPC, than for POPC and DPPC. QENS studies, over the temperature range 283–323K, showed that the resulting data were best modelled by two Lorentzian functions: a narrow component, describing the “in-plane” lipid diffusion, and a broader component, describing the lipid alkyl chain segmental relaxation. The overall “in-plane” diffusion was found to show a significant reduction upon increasing temperature due to the vesicle membranes transitioning from one containing rafts to one where the component lipids are homogeneously mixed. The use of different isotopic combinations allowed the measured overall reduction of in-plane diffusion to be understood in terms of an increase in diffusion of the saturated DPPC lipid and a corresponding decrease in diffusion of the unsaturated DOPC/POPC lipid. As the rafts are considered to be composed principally of saturated lipid and cholesterol, the breakdown of rafts decreases the exposure of the DPPC to cholesterol whilst increasing the exposure of cholesterol to unsaturated lipid. These results show the sensitivity of lipid diffusion to local cholesterol concentration, and the importance of considering the local, rather that the global composition of a membrane when understanding the diffusion processes of lipids within the membrane. The novel combination of SANS and QENS allows a non-intrusive approach to characterize the structure and dynamics occurring in phase-separated model membranes which are designed to mimic the lateral heterogeneity of lipids seen in cellular membranes–a heterogeneity that can have pathological consequences.
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| 6. |
- Bello, Gianluca, et al.
(author)
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Characterization of the aggregates formed by various bacterial lipopolysaccharides in solution and upon interaction with antimicrobial peptides
- 2015
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In: Langmuir. - : American Chemical Society (ACS). - 0743-7463 .- 1520-5827. ; 31:2, s. 741-751
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Journal article (peer-reviewed)abstract
- The biophysical analysis of the aggregates formed by different chemotypes of bacterial lipopolysaccharides (LPS) before and after challenge by two different anti-endotoxic antimicrobial peptides (LL37 and bovine lactoferricin), was performed in order to determine their effect on the morphology of LPS aggregates. Small-angle neutron scattering (SANS) and cryogenic transmission electron microscopy (cryoTEM) were used to examine the structures formed by both smooth and rough LPS chemotypes and the effect of the peptides, by visualization of the aggregates and analysis of the scattering data by means of both mathematical approximations and defined models. The data showed that the structure of LPS determines the morphology of the aggregates and inuences the binding activity of both peptides. The morphologies of the worm-like micellar aggregates formed by the smooth LPS were relatively unaltered by the presence of the peptides due to their pre-existing high degree of positive curvature being little affected by their association with either peptide. On the other hand the aggregates formed by the rough LPS chemotypes, showed marked morphological changes from lamellar structures to ordered micellar networks, induced by the increase in positive curvature engendered upon association with the peptides. The combined use of cryoTEM and SANS proved to be a very useful tool for studying the aggregation properties of LPS in solution at biologically relevant concentrations.
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| 7. |
- Cárdenas, Marité, et al.
(author)
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Review of structural design guiding the development of lipid nanoparticles for nucleic acid delivery
- 2023
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In: Current Opinion in Colloid and Interface Science. - : Elsevier. - 1359-0294 .- 1879-0399. ; 66
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Research review (peer-reviewed)abstract
- Lipid nanoparticles (LNPs) are the most versatile and successful gene delivery systems, notably highlighted by their use in vaccines against COVID-19. LNPs have a well-defined core–shell structure, each region with its own distinctive compositions, suited for a wide range of in vivo delivery applications. Here, we discuss how a detailed knowledge of LNP structure can guide LNP formulation to improve the efficiency of delivery of their nucleic acid payload. Perspectives are detailed on how LNP structural design can guide more efficient nucleic acid transfection. Views on key physical characterization techniques needed for such developments are outlined including opinions on biophysical approaches both correlating structure with functionality in biological fluids and improving their ability to escape the endosome and deliver they payload.
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| 8. |
- Saaka, Yussif, et al.
(author)
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Characterisation of the apparent aqueous solubility enhancement of testosterone analogues in micelles of dodecyl-chained surfactants with different headgroups
- 2023
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In: Journal of Molecular Liquids. - 0167-7322. ; 385
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Journal article (peer-reviewed)abstract
- The solubilisation capacities of the micelles formed by a range of surfactants possessing a dodecyl (C12) hydrocarbon ‘tail’ and a variety of hydrophilic ‘headgroups’ have been studied for a range of hydrophobic steroids (testosterone (T) and its propionate (TP) and enanthate (TE) esters). The solubilisation studies were performed at ambient temperature, with drug concentration monitored (over 48–72 h) by UV absorbance. The various surfactant systems were characterised in terms of their physicochemical properties, including their surface tension, critical micelle concentration, viscosity, and density. Results show that while the apparent aqueous solubility of the poorly water-soluble steroids increases upon solubilisation within the surfactant micelles, the extent of this increase varies with the nature of the hydrophilic headgroup and the hydrophobicity of the drug. Specifically, changing the surfactant headgroup from non-ionic to zwitterionic, then to ionic, results in a marked increase in solubility of the two least hydrophobic steroids, testosterone and testosterone propionate, suggesting rather counter-intuitively that these steroidal drugs tend to associate to a greater extent with micelles formed by surfactants with more hydrophilic/charged head groups. The more hydrophobic steroid, TE, was solubilised to the greatest extent, being predominantly solubilised within the micelle core. In this case, the influence of surfactant head group on TE solubilisation was less obvious, with surfactants containing ionic and zwitterionic head groups exhibiting high levels of solubilisation. The physicochemical properties that had most influence on solubilisation of the testosterone analogues, as evaluated using multiple linear regression, were micelle shape for T and TP, and critical micelle concentration for TE. Through the findings of this comparative study, the essential molecular descriptors of optimal solubilisation for improved drug delivery and the loci of solubilisation of the testosterone analogues have been identified.
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