| 1. |
- Vecchio, Federica, et al.
(författare)
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Abnormal neutrophil signature in the blood and pancreas of presymptomatic and symptomatic type 1 diabetes
- 2018
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Ingår i: JCI Insight. - : American Society for Clinical Investigation. - 2379-3708. ; 3:18
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Neutrophils and their inflammatory mediators are key pathogenic components in multiple autoimmune diseases, while their role in human type 1 diabetes (T1D), a disease that progresses sequentially through identifiable stages prior to the clinical onset, is not well understood. We previously reported that the number of circulating neutrophils is reduced in patients with T1D and in presymptomatic at-risk subjects. The aim of the present work was to identify possible changes in circulating and pancreas-residing neutrophils throughout the disease course to better elucidate neutrophil involvement in human T1D.METHODS: Data collected from 389 subjects at risk of developing T1D, and enrolled in 4 distinct studies performed by TrialNet, were analyzed with comprehensive statistical approaches to determine whether the number of circulating neutrophils correlates with pancreas function. To obtain a broad analysis of pancreas-infiltrating neutrophils throughout all disease stages, pancreas sections collected worldwide from 4 different cohorts (i.e., nPOD, DiViD, Siena, and Exeter) were analyzed by immunohistochemistry and immunofluorescence. Finally, circulating neutrophils were purified from unrelated nondiabetic subjects and donors at various T1D stages and their transcriptomic signature was determined by RNA sequencing.RESULTS: Here, we show that the decline in β cell function is greatest in individuals with the lowest peripheral neutrophil numbers. Neutrophils infiltrate the pancreas prior to the onset of symptoms and they continue to do so as the disease progresses. Of interest, a fraction of these pancreas-infiltrating neutrophils also extrudes neutrophil extracellular traps (NETs), suggesting a tissue-specific pathogenic role. Whole-transcriptome analysis of purified blood neutrophils revealed a unique molecular signature that is distinguished by an overabundance of IFN-associated genes; despite being healthy, said signature is already present in T1D-autoantibody-negative at-risk subjects.CONCLUSIONS: These results reveal an unexpected abnormality in neutrophil disposition both in the circulation and in the pancreas of presymptomatic and symptomatic T1D subjects, implying that targeting neutrophils might represent a previously unrecognized therapeutic modality.FUNDING: Juvenile Diabetes Research Foundation (JDRF), NIH, Diabetes UK.
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| 2. |
- Cárdenas, Marité, et al.
(författare)
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Review of structural design guiding the development of lipid nanoparticles for nucleic acid delivery
- 2023
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Ingår i: Current Opinion in Colloid and Interface Science. - : Elsevier. - 1359-0294 .- 1879-0399. ; 66
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Forskningsöversikt (refereegranskat)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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| 3. |
- Clifton, Luke A, et al.
(författare)
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Design and use of model membranes to study biomolecular interactions using complementary surface-sensitive techniques.
- 2020
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Ingår i: Advances in Colloid and Interface Science. - : Elsevier. - 0001-8686 .- 1873-3727. ; 277
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Tidskriftsartikel (refereegranskat)abstract
- Cellular membranes are complex structures and simplified analogues in the form of model membranes or biomembranes are used as platforms to understand fundamental properties of the membrane itself as well as interactions with various biomolecules such as drugs, peptides and proteins. Model membranes at the air-liquid and solid-liquid interfaces can be studied using a range of complementary surface-sensitive techniques to give a detailed picture of both the structure and physicochemical properties of the membrane and its resulting interactions. In this review, we will present the main planar model membranes used in the field to date with a focus on monolayers at the air-liquid interface, supported lipid bilayers at the solid-liquid interface and advanced membrane models such as tethered and floating membranes. We will then briefly present the principles as well as the main type of information on molecular interactions at model membranes accessible using a Langmuir trough, quartz crystal microbalance with dissipation monitoring, ellipsometry, atomic force microscopy, Brewster angle microscopy, Infrared spectroscopy, and neutron and X-ray reflectometry. A consistent example for following biomolecular interactions at model membranes is used across many of the techniques in terms of the well-studied antimicrobial peptide Melittin. The overall objective is to establish an understanding of the information accessible from each technique, their respective advantages and limitations, and their complementarity.
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| 4. |
- Gilbert, Jennifer, et al.
(författare)
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Evolution of the structure of lipid nanoparticles for nucleic acid delivery : From in situ studies of formulation to colloidal stability
- 2024
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Ingår i: Journal of Colloid and Interface Science. - 0021-9797. ; 660, s. 66-76
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Tidskriftsartikel (refereegranskat)abstract
- The development of lipid nanoparticle (LNP) based therapeutics for delivery of RNA has triggered the advance of new strategies for formulation, such as high throughput microfluidics for precise mixing of components into well-defined particles. In this study, we have characterised the structure of LNPs throughout the formulation process using in situ small angle x-ray scattering in the microfluidic chip, then by sampling in the subsequent dialysis process. The final formulation was investigated with small angle x-ray (SAXS) and neutron (SANS) scattering, dynamic light scattering (DLS) and cryo-TEM. The effect on structure was investigated for LNPs with a benchmark lipid composition and containing different cargos: calf thymus DNA (DNA) and two model mRNAs, polyadenylic acid (polyA) and polyuridylic acid (polyU). The LNP structure evolved during mixing in the microfluidic channel, however was only fully developed during the dialysis. The colloidal stability of the final formulation was affected by the type of incorporated nucleic acids (NAs) and decreased with the degree of base-pairing, as polyU induced extensive particle aggregation. The main NA LNP peak in the SAXS data for the final formulation were similar, with the repeat distance increasing from polyU
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| 5. |
- Luchini, Alessandra, et al.
(författare)
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Dark peptide discs for the investigation of membrane proteins in supported lipid bilayers : the case of synaptobrevin 2 (VAMP2)
- 2022
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Ingår i: Nanoscale Advances. - : Royal Society of Chemistry. - 2516-0230. ; 10:17
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Tidskriftsartikel (refereegranskat)abstract
- Supported lipid bilayers (SLBs) are commonly used as model systems mimicking biological membranes. Recently, we reported a new method to produce SLBs with incorporated membrane proteins, which is based on the application of peptide discs [Luchini et al., Analytical Chemistry, 2020, 92, 1081-1088]. Peptide discs are small discoidal particles composed of a lipid core and an outer belt of self-assembled 18A peptides. SLBs including membrane proteins can be formed by depositing the peptide discs on a solid support and subsequently removing the peptide by buffer rinsing. Here, we introduce a new variant of the 18A peptide, named dark peptide (d18A). d18A exhibits UV absorption at 214 nm, whereas the absorption at 280 nm is negligible. This improves sample preparation as it enables a direct quantification of the membrane protein concentration in the peptide discs by measuring UV absorption at 280 nm. We describe the application of the peptide discs prepared with d18A (dark peptide discs) to produce SLBs with a membrane protein, synaptobrevin 2 (VAMP2). The collected data showed the successful formation of SLBs with high surface coverage and incorporation of VAMP2 in a single orientation with the extramembrane domain exposed towards the bulk solvent. Compared to 18A, we found that d18A was more efficiently removed from the SLB. Our data confirmed the structural organisation of VAMP2 as including both alpha-helical and beta-sheet secondary structure. We further verified the orientation of VAMP2 in the SLBs by characterising the binding of VAMP2 with alpha-synuclein. These results point at the produced SLBs as relevant membrane models for biophysical studies as well as nanostructured biomaterials.
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| 6. |
- Luchini, Alessandra, et al.
(författare)
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Peptide discs as precursors of biologically relevant supported lipid bilayers
- 2021
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Ingår i: Journal of Colloid and Interface Science. - : Elsevier. - 0021-9797 .- 1095-7103. ; 585, s. 376-385
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Tidskriftsartikel (refereegranskat)abstract
- Supported lipid bilayers (SLBs) are commonly used to investigate the structure and dynamics of biological membranes. Vesicle fusion is a widely exploited method to produce SLBs. However, this process becomes less favoured when the vesicles contain complex lipid mixtures, e.g. natural lipid extracts. In these cases, it is often necessary to change experimental parameters, such as temperature, to unphysiological values to trigger the SLB formation. This may induce lipid degradation and is also not compatible with including membrane proteins or other biomolecules into the bilayers. Here, we show that the peptide discs, ~10 nm discoidal lipid bilayers stabilized in solution by a self-assembled 18A peptide belt, can be used as precursors for SLBs. The characterizations by means of neutron reflectometry and attenuated total reflectance-FTIR spectroscopy show that SLBs were successfully formed both from synthetic lipid mixtures (surface coverage 90-95%) and from natural lipid mixtures (surface coverage ~85%). Traces of 18A peptide (below 0.02 M ratio) left at the support surface after the bilayer formation do not affect the SLB structure. Altogether, we demonstrate that peptide disc formation of SLBs is much faster than the SLB formation by vesicle fusion and without the need of altering any experimental variable from physiologically relevant values.
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| 7. |
- Ongun, Melike, et al.
(författare)
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Lipid nanoparticles for local delivery of mRNA to the respiratory tract : Effect of PEG-lipid content and administration route
- 2024
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Ingår i: European Journal of Pharmaceutics and Biopharmaceutics. - 0939-6411. ; 198
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Tidskriftsartikel (refereegranskat)abstract
- Design of inhalable mRNA therapeutics is promising because local administration in the respiratory tract is minimally invasive and induces a local response. However, several challenges related to administration via inhalation and respiratory tract barriers have so far prevented the progress of inhaled mRNA therapeutics. Here, we investigated factors of importance for lipid nanoparticle (LNP)-mediated delivery of mRNA to the respiratory tract. We hypothesized that: (i) the PEG-lipid content is important for providing colloidal stability during aerosolization and for mucosal delivery, (ii) the PEG-lipid content influences the expression of mRNA-encoded protein in the lungs, and (iii) the route of administration (nasal versus pulmonary) affects mRNA delivery in the lungs. In this study, we aimed to optimize the PEG-lipid content for mucosal delivery and to investigate the effect of administration route on the kinetics of protein expression. Our results show that increasing the PEG-lipid content improves the colloidal stability during the aerosolization process, but has a negative impact on the transfection efficiency in vitro. The kinetics of protein expression in vivo is dependent on the route of administration, and we found that pulmonary administration of mRNA-LNPs to mice results in more durable protein expression than nasal administration. These results demonstrate that the design of the delivery system and the route of administration are important for achieving high mRNA transfection efficiency in the respiratory tract.
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| 8. |
- Pfrang, Christian, et al.
(författare)
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Ozonolysis of methyl oleate monolayers at the air-water interface: oxidation kinetics, reaction products and atmospheric implications
- 2014
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Ingår i: Physical Chemistry Chemical Physics. - : Royal Society of Chemistry (RSC). - 1463-9084. ; 16:26, s. 13220-13228
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Tidskriftsartikel (refereegranskat)abstract
- Ozonolysis of methyl oleate monolayers at the air-water interface results in surprisingly rapid loss of material through cleavage of the C=C bond and evaporation/ dissolution of reaction products. We determine using neutron reflectometry a rate coefficient of (5.7 +/- 0.9) x 10(-10) cm(2) molecule(-1) s(-1) and an uptake coefficient of similar to 3 x 10(-5) for the oxidation of a methyl ester monolayer: the atmospheric lifetime is similar to 10 min. We obtained direct experimental evidence that <2% of organic material remains at the surface on atmospheric timescales. Therefore known long atmospheric residence times of unsaturated fatty acids suggest that these molecules cannot be present at the interface throughout their ageing cycle, i.e. the reported atmospheric longevity is likely to be attributed to presence in the bulk and viscosity-limited reactive loss. Possible reaction products were characterized by ellipsometry and uncertainties in the atmospheric fate of organic surfactants such as oleic acid and its methyl ester are discussed. Our results suggest that a minor change to the structure of the molecule (fatty acid vs. its methyl ester) considerably impacts on reactivity and fate of the organic film.
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| 9. |
- Sebastiani, Federica, et al.
(författare)
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Apolipoprotein E Binding Drives Structural and Compositional Rearrangement of mRNA-Containing Lipid Nanoparticles
- 2021
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Ingår i: ACS Nano. - : American Chemical Society (ACS). - 1936-0851 .- 1936-086X. ; 15:4, s. 6709-6722
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Tidskriftsartikel (refereegranskat)abstract
- Emerging therapeutic treatments based on the production of proteins by delivering mRNA have become increasingly important in recent times. While lipid nanoparticles (LNPs) are approved vehicles for small interfering RNA delivery, there are still challenges to use this formulation for mRNA delivery. LNPs are typically a mixture of a cationic lipid, distearoylphosphatidylcholine (DSPC), cholesterol, and a PEG-lipid. The structural characterization of mRNA-containing LNPs (mRNA-LNPs) is crucial for a full understanding of the way in which they function, but this information alone is not enough to predict their fate upon entering the bloodstream. The biodistribution and cellular uptake of LNPs are affected by their surface composition as well as by the extracellular proteins present at the site of LNP administration, e.g., apolipoproteinE (ApoE). ApoE, being responsible for fat transport in the body, plays a key role in the LNP’s plasma circulation time. In this work, we use small-angle neutron scattering, together with selective lipid, cholesterol, and solvent deuteration, to elucidate the structure of the LNP and the distribution of the lipid components in the absence and the presence of ApoE. While DSPC and cholesterol are found to be enriched at the surface of the LNPs in buffer, binding of ApoE induces a redistribution of the lipids at the shell and the core, which also impacts the LNP internal structure, causing release of mRNA. The rearrangement of LNP components upon ApoE incubation is discussed in terms of potential relevance to LNP endosomal escape.
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| 10. |
- Sebastiani, Federica, et al.
(författare)
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Night-time oxidation at the air-water interface : co-surfactant effects in binary mixtures
- 2022
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Ingår i: Environmental Science. - : Royal Society of Chemistry. - 2634-3606. ; :6, s. 1324-1337
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Tidskriftsartikel (refereegranskat)abstract
- The ageing of organic-coated aqueous aerosols at night is investigated by reacting NO3 with binary surfactant mixtures floating on water. The surfactants are oleic acid (OA), methyl oleate (MO) and stearic acid (SA). Deuterated surfactants mixed with hydrogenous surfactants were studied using neutron reflectometry to determine the reaction kinetics of organic two-component monolayers with NO3 at the air-water interface for the first time. We measured the rate coefficients for OA monolayers, mixed with hydrogenous co-surfactant MO or SA to be (3 +/- 1) x 10-8 cm2 per molecule per s or (3.6 +/- 0.9) x 10-8 cm2 per molecule per s and MO monolayers mixed with hydrogenous co-surfactant OA or SA to be (0.7 +/- 0.4) x 10-8 cm2 per molecule per s or (3 +/- 1) x 10-8 cm2 per molecule per s. The initial desorption lifetimes of NO3, taud,NO3,1, were 8 +/- 3 ns, 14 +/- 4 ns, 12 +/- 3 ns and 21 +/- 10 ns. The approximately doubled desorption lifetime for MO-SA compared to the other mixtures is consistent with a more accessible double bond associated with the larger area per molecule of MO in the presence of SA facilitating NO3 attack. The significantly slower reactive loss of MO-OA compared to a MO monolayer demonstrates that multi-component surfactant mixtures need to be studied in addition to single-component monolayers. Such a retarded decay would cause the residence time to change from ca. 4 to 22 minutes associated with increased transport distances of surfactant species together with any other pollutants that may be protected underneath the surfactant film.
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| 11. |
- Sebastiani, Federica, et al.
(författare)
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Nighttime oxidation of surfactants at the air-water interface : effects of chain length, head group and saturation
- 2018
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Ingår i: Atmospheric Chemistry And Physics. - : European Geosciences Union (EGU). - 1680-7316 .- 1680-7324. ; 18:5, s. 3249-3268
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Tidskriftsartikel (refereegranskat)abstract
- Reactions of the key atmospheric nighttime oxidant NO3 with organic monolayers at the air-water interface are used as proxies for the ageing of organic-coated aqueous aerosols. The surfactant molecules chosen for this study are oleic acid (OA), palmitoleic acid (POA), methyl oleate ( MO) and stearic acid ( SA) to investigate the effects of chain length, head group and degree of unsaturation on the reaction kinetics and products formed. Fully and partially deuterated surfactants were studied using neutron reflectometry (NR) to determine the reaction kinetics of organic monolayers with NO3 at the air-water interface for the first time. Kinetic modelling allowed us to determine the rate coefficients for the oxidation of OA, POA and MO monolayers to be (2.8 +/- 0.7) x 10(-8), (2.4 +/- 0.5) x 10(-8) and (3.3 +/- 0.6) x 10(-8) cm(2) molecule(-1) s(-1) for fitted initial desorption lifetimes of NO3 at the closely packed organic monolayers, tau(d), NO3, 1, of 8.1 +/- 4.0, 16 +/- 4.0 and 8.1 +/- 3.0 ns, respectively. The approximately doubled desorption lifetime found in the best fit for POA compared to OA and MO is consistent with a more accessible double bond associated with the shorter alkyl chain of POA facilitating initial NO3 attack at the double bond in a closely packed monolayer. The corresponding uptake coefficients for OA, POA and MO were found to be (2.1 +/- 0.5) x 10(-3), (1.7 +/- 0.3) x 10(-3) and (2.1 +/- 0.4) x 10(-3), respectively. For the much slower NO3-initiated oxidation of the saturated surfactant SA we estimated a loss rate of approximately (5 +/- 1) x 10(-12) cm(2) molecule(-1) s(-1), which we consider to be an upper limit for the reactive loss, and estimated an uptake coefficient of ca, (5 +/- 1) x 10(-7). Our investigations demonstrate that NO3 will contribute substantially to the processing of unsaturated surfactants at the air-water interface during nighttime given its reactivity is ca. 2 orders of magnitude higher than that of O-3. Furthermore, the relative contributions of NO3 and O-3 to the oxidative losses vary massively between species that are closely related in structure: NO3 reacts ca. 400 times faster than O-3 with the common model surfactant oleic acid, but only ca. 60 times faster with its methyl ester MO. It is therefore necessary to perform a case-by-case assessment of the relative contributions of the different degradation routes for any specific surfactant. The overall impact of NO3 on the fate of saturated surfactants is slightly less clear given the lack of prior kinetic data for comparison, but NO3 is likely to contribute significantly to the loss of saturated species and dominate their loss during nighttime. The retention of the organic character at the air-water interface differs fundamentally between the different surfactant species: the fatty acids studied (OA and POA) form products with a yield of similar to 20% that are stable at the interface while NO3=initiated oxidation of the methyl ester MO rapidly and effectively removes the organic character (<= 3% surface-active products). The film-forming potential of reaction products in real aerosol is thus likely to depend on the relative proportions of saturated and unsaturated surfactants as well as the head group properties. Atmospheric lifetimes of unsaturated species are much longer than those determined with respect to their reactions at the air-water interface, so they must be protected from oxidative attack, for example, by incorporation into a complex aerosol matrix or in mixed surface films with yet unexplored kinetic behaviour.
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| 12. |
- Sebastiani, Federica, et al.
(författare)
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Screening of the binding affinity of serum proteins to lipid nanoparticles in a cell free environment
- 2021
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Ingår i: Journal of Colloid and Interface Science. - : Elsevier. - 0021-9797 .- 1095-7103. ; 610, s. 766-774
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Tidskriftsartikel (refereegranskat)abstract
- Lipid nanoparticles (LNPs) are promising drug and gene carriers. Upon intravenous administration, LNPs' experience different degree of cellular uptake depending on their formulation. Currently, in vitro and in vivo studies are the gold standard for assessing the fate of nano carriers once administered, but they are time consuming and expensive. In this work, we propose a time and cost-effective method to screen a wide range of LNP formulations and select the most promising candidates for in vitro and in vivo studies. Two different approaches were explored to investigate the binding affinity between LNPs and serum proteins using sensor functionalisation with either protein specific antibody or PEG specific antibody. The first approach allowed to identify the presence of a specific protein in the protein corona of lipid particles (reconstituted and native high-density lipoproteins (rHDL and HDL), and low-density lipoproteins LDL); while the second one provided a versatile platform for the immobilisation of pegylated-particles in order to follow the interaction with serum proteins and hence predict the composition of LNP protein corona. Sensing was done using Quartz Crystal Microbalance with Dissipation (QCM-D) but the approach is extendable to other surface sensing techniques such as Surface Plasmon Resonance (SPR) or ellipsometry.
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| 13. |
- Tummino, Andrea, et al.
(författare)
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Effects of Aggregate Charge and Subphase Ionic Strength on the Properties of Spread Polyelectrolyte/Surfactant Films at the Air/Water Interface under Static and Dynamic Conditions
- 2018
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Ingår i: Langmuir. - : American Chemical Society (ACS). - 0743-7463 .- 1520-5827. ; 34:6, s. 2312-2323
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Tidskriftsartikel (refereegranskat)abstract
- We demonstrate the ability to tune the formation of extended structures in films of poly(sodium styrenesulfonate)/dodecyltrimethylammonium bromide at the air/water interface through control over the charge/structure of aggregates as well as the ionic strength of the subphase. Our methodology to prepare loaded polyelectrolyte/surfactant films from self-assembled liquid crystalline aggregates exploits their fast dissociation and Marangoni spreading of material upon contact with an aqueous subphase. This process is proposed as a potential new route to prepare cheap biocompatible films for transfer applications. We show that films spread on water from Marangoni swollen aggregates of low/negative charge have 1:1 charge Spreading binding and can be compressed only to a monolayer, beyond which material is lost to the bulk. For films spread on water from compact aggregates of positive charge, however, extended structures of the two components are created upon spreading or upon compression of the film beyond a monolayer. The application of ellipsometry, Brewster angle microscopy, and neutron reflectometry as well as measurements of surface pressure isotherms allow us to reason that formation of extended structures is activated by aggregates embedded in the film. The situation upon spreading on 0.1 M NaCl is different as there is a high concentration of small ions that stabilize loops of the polyelectrolyte upon film compression, yet extended structures of both components are only transient. Analogy of the controlled formation of extended structures in fluid monolayers is made to reservoir dynamics in lung surfactant. The work opens up the possibility to control such film dynamics in related systems through the rational design of particles in the future.
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| 14. |
- Waldie, Sarah, et al.
(författare)
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ApoE and ApoE Nascent-Like HDL Particles at Model Cellular Membranes : Effect of Protein Isoform and Membrane Composition
- 2021
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Ingår i: Frontiers in Chemistry. - : Frontiers Media S.A.. - 2296-2646. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Apolipoprotein E (ApoE), an important mediator of lipid transportation in plasma and the nervous system, plays a large role in diseases such as atherosclerosis and Alzheimer's. The major allele variants ApoE3 and ApoE4 differ only by one amino acid. However, this difference has major consequences for the physiological behaviour of each variant. In this paper, we follow (i) the initial interaction of lipid-free ApoE variants with model membranes as a function of lipid saturation, (ii) the formation of reconstituted High-Density Lipoprotein-like particles (rHDL) and their structural characterisation, and (iii) the rHDL ability to exchange lipids with model membranes made of saturated lipids in the presence and absence of cholesterol [1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) or 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) with and without 20 mol% cholesterol]. Our neutron reflection results demonstrate that the protein variants interact differently with the model membranes, adopting different protein conformations. Moreover, the ApoE3 structure at the model membrane is sensitive to the level of lipid unsaturation. Small-angle neutron scattering shows that the ApoE containing lipid particles form elliptical disc-like structures, similar in shape but larger than nascent or discoidal HDL based on Apolipoprotein A1 (ApoA1). Neutron reflection shows that ApoE-rHDL do not remove cholesterol but rather exchange saturated lipids, as occurs in the brain. In contrast, ApoA1-containing particles remove and exchange lipids to a greater extent as occurs elsewhere in the body.
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| 15. |
- Waldie, Sarah, et al.
(författare)
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Lipoprotein ability to exchange and remove lipids from model membranes as a function of fatty acid saturation and presence of cholesterol.
- 2020
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Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier. - 1388-1981 .- 1879-2618. ; 1865:10
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Tidskriftsartikel (refereegranskat)abstract
- Lipoproteins play a central role in the development of atherosclerosis. High and low-density lipoproteins (HDL and LDL), known as 'good' and 'bad' cholesterol, respectively, remove and/or deposit lipids into the artery wall. Hence, insight into lipid exchange processes between lipoproteins and cell membranes is of particular importance in understanding the onset and development of cardiovascular disease. In order to elucidate the impact of phospholipid tail saturation and the presence of cholesterol in cell membranes on these processes, neutron reflection was employed in the present investigation to follow lipid exchange with both HDL and LDL against model membranes. Mirroring clinical risk factors for the development of atherosclerosis, lower exchange was observed in the presence of cholesterol, as well as for an unsaturated phospholipid, compared to faster exchange when using a fully saturated phospholipid. These results highlight the importance of membrane composition on the interaction with lipoproteins, chiefly the saturation level of the lipids and presence of cholesterol, and provide novel insight into factors of importance for build-up and reversibility of atherosclerotic plaque. In addition, the correlation between the results and well-established clinical risk factors suggests that the approach taken can be employed also for understanding a broader set of risk factors including, e.g., effects of triglycerides and oxidative stress, as well as local effects of drugs on atherosclerotic plaque formation.
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