340 research outputs found

    Review of structural design guiding the development of lipid nanoparticles for nucleic acid delivery

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    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

    The Effect of Structured Exercise Classes and a Lifestyle Intervention on Cardiovascular Risk Factors in Primary Schoolchildren: An Exploratory Trial (The A-CLASS Project)

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    This exploratory trial evaluates the effect of a structured exercise (STEX) or lifestyle intervention (PASS) program upon cardiovascular (CV) disease risk factors in children. Sixty-one schoolchildren were randomly assigned by school to an intervention or control (CON) condition. The effect of the STEX (compared with CON) was a mean benefit of -0.018 mm for average maximum carotid intima-media thickness. The PASS intervention did not result in clinically important effects, and no other substantial changes were observed. Relatively high probability of clinically beneficial effects of the STEX intervention suggests that a larger, definitive randomized trial with longer follow-up is warranted

    Review of the effectiveness of current community ownership mechanisms and of options for supporting the expansion of community ownership in Scotland

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    This report presents the findings of research commissioned by the Scottish Land Commission to review the effectiveness of community ownership mechanisms and options for simplifying or improving these mechanisms to enable and support the expansion of community ownership in Scotland. This included reviewing processes relating to negotiated sales or transfers of land and/or assets to communities, as well as legislative mechanisms including the Community Right to Buy (CRtB), Crofting Community Right to Buy, the Transfer of Crofting Estates (Scotland) Act 1997 and Asset Transfer measures under the Community Empowerment (Scotland) Act 2015

    Nucleic Acid-Loaded Lipid Nanoparticle Interactions with Model Endosomal Membranes

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    [Image: see text] Lipid nanoparticles (LNPs) are important delivery systems for RNA-based therapeutics, yet the mechanism of their interaction with endosomal membranes remains unclear. Here, the interactions of nucleic acid-loaded LNPs that contain an ionizable lipid with models of the early and late endosomal membranes are studied, for the first time, using different reflectometry techniques. Novel insight is provided with respect to the subphase pH, the stage of the endosome, and the nature of the nucleic acid cargo. It is found that the insertion of lipids from the LNPs into the model membrane is greatest at pH 6.5 and 5.5, whereas at higher pH, lipid insertion is suppressed with evidence instead for the binding of intact LNPs, demonstrating the importance of the pH in the fusion of LNPs undergoing the endosomal pathway. Furthermore, and independently of the pH, the effect of the early- versus late-stage endosomal models is minimal, suggesting that the increased fluidity and anionic nature of the late endosome has little effect on the extent of LNP interaction. Last, there is greater nucleic acid delivery from LNPs containing mRNA than Poly(A), indicating that the extent of interaction can be tuned according to the nature of the nucleic acid cargo. Such new information on the relative impact of factors influencing nucleic acid delivery by LNP interactions with endosomal membranes is important in the design and tuning of vehicles with improved nucleic acid delivery capacities

    Summer crops: relative water use efficiencies and legacy impacts in farming systems

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    Take home message • While summer crops offer rotational options in the farming system, choose the correct crop to match your available soil water and crop history • Sorghum is a reliable performer often exceeding other options in terms of returnedpermmused•CottonandmaizerequirehigherwateravailabilityandproducelessreliableWUE( returned per mm used • Cotton and maize require higher water availability and produce less reliable WUE (/mm). However, cotton has legacy impacts on water availability for subsequent crops that should be considered • Mungbean can produce higher /mminlowwateravailabilitysituations(150mmofplantavailablewaterwillmaximisecropWUEandprofitability.Everyextrammatsowingcouldbeworthasmuchas/mm in low water availability situations ( 150 mm of plant available water will maximise crop WUE and profitability. Every extra mm at sowing could be worth as much as 35-70 extra return/ha • Higher density sorghum crops may provide greater crop competition against weeds and potential upside yield benefits in good season. We have seen limited legacy benefits (e.g. improved ground cover) or costs (e.g. greater soil water/nutrient extraction) for soil water or nutrient availability

    Nitrogen and water dynamics in farming systems – multi-year impact of crop sequences

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    Take home messages • Grain legumes have utilised soil mineral nitrogen (N) to the same extent as cereal crops and have higher N export which often offsets N fixation inputs • Additional applied N reduced the depletion of background soil mineral N status at most sites; we are recovering a high percentage (>50%) in soil mineral pool. • Application of ~50 t/ha of compost or manure (10 t/ha OC) coupled with N fertiliser rates for 90th percentile yield potential has dramatically increased the soil mineral N in four years • Decreasing cropping frequency has reduced N export and so stored more N over the longer fallows, which has reduced N fertiliser requirements for following crops • Long fallows are mineralising N and moving N down the soil profile even under some very dry conditions • Most excess N is not lost in the system rather it is moved down the soil profile for future crops • The marginal WUE of crops (i.e. the grain yield increase per extra mm of available water) is lower when crops have less than 100 mm prior to planting. Hence, waiting until soil moisture reaches these levels is critical to maximise conversion of accumulated soil moisture into grain • The previous crop influences the efficiency of fallow water accumulation with winter cereals > sorghum > pulses. Long fallows are also less efficient than shorter fallows (<8 months). This has implications for assuming how much soil moisture may have accumulated during fallows

    Understanding and optimising the transfection of lipopolyplexes formulated in saline: the effects of peptide and serum

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    Lipopolyplexes (LPDs) are of considerable interest for use as gene delivery vehicles. Here LPDs have been prepared from cationic vesicles (composed of a 1 : 1 molar ratio of DOTMA with the neutral helper lipid, DOPE), singly branched cationic peptides and plasmid DNA. All peptides contained a linker sequence (cleaved by endosomal furin) attached to a targeting sequence selected to bind human airway epithelial cells and mediate gene delivery. The current study investigates the effects of novel Arg-containing cationic peptide sequences on the biophysical and transfection properties of LPDs. Mixed His/Arg cationic peptides were of particular interest, as these sequences have not been previously used in LPD formulations. Lengthening the number of cationic residues in a homopolymer from 6 to 12 in each branch reduced transfection using LPDs, most likely due to increased DNA compaction hindering the release of pDNA within the target cell. Furthermore, LPDs containing mixed Arg-containing peptides, particularly an alternating Arg/His sequence exhibited an increase in transfection, probably because of their optimal ability to complex and subsequently release pDNA. To confer stability in serum, LPDs were prepared in 0.12 M sodium chloride solution (as opposed to the more commonly used water) yielding multilamellar LPDs with very high levels of size reproducibility and DNA protection, especially when compared to the (unilamellar) LPDs formed in water. Significantly for the clinical applications of the LPDs, those prepared in the presence of sodium chloride retained high levels of transfection in the presence of media supplemented with fetal bovine serum. This work therefore represents a significant advance for the optimisation of LPD formulation for gene delivery, under physiologically relevant conditions, in vivo
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