1,451 research outputs found
Swimming in the Deep End: Youths’ Social, Material, and Bodily Senses of Immersion in an English Competitive Swimming Club
Disjuncture as Well-Being in Youth Swimming:The Effects of the COVID-19 Pandemic on Everyday Associations and Routines
Falling Short:Response to UKRI’s Phase 1 and Phase 2 Support for PhD researchers During the COVID-19 Pandemic
A Workflow for Lipid Nanoparticle (LNP) Formulation Optimization Using Designed Mixture-Process Experiments and Self-Validated Ensemble Models (SVEM)
We present a Quality by Design (QbD) styled approach for optimizing lipid
nanoparticle (LNP) formulations, aiming to offer scientists an accessible
workflow. The inherent restriction in these studies, where the molar ratios of
ionizable, helper, and PEG lipids must add up to 100%, requires specialized
design and analysis methods to accommodate this mixture constraint. Focusing on
lipid and process factors that are commonly used in LNP design optimization, we
provide steps that avoid many of the difficulties that traditionally arise in
the design and analysis of mixture-process experiments by employing
space-filling designs and utilizing the recently developed statistical
framework of self-validated ensemble models (SVEM). In addition to producing
candidate optimal formulations, the workflow also builds graphical summaries of
the fitted statistical models that simplify the interpretation of the results.
The newly identified candidate formulations are assessed with confirmation runs
and optionally can be conducted in the context of a more comprehensive
second-phase study
(-)-Epigallocatechin-3-gallate (EGCG) maintains k-casein in its pre-fibrillar state without redirecting its aggregation pathway
The polyphenol (-)-epigallocatechin-3-gallate (EGCG) has recently attracted much research interest in the field of protein-misfolding diseases because of its potent anti-amyloid activity against amyloid-beta, alpha-synuclein and huntingtin, the amyloid-fibril-forming proteins involved in Alzheimer\u27s, Parkinson\u27s and Huntington\u27s diseases, respectively. EGCG redirects the aggregation of these polypeptides to a disordered off-folding pathway that results in the formation of non-toxic amorphous aggregates. whether this anti-fibril activity is specific to these disease-related target proteins or ismore generic remains to be established. In addition, the mechanism by which EGCG exerts its effects, as with all anti-amyloidogenic polyphenols, remains unclear. To address these aspects, we have investigated the ability of EGCG to inhibit amyloidogenesis of the generic model fibril-forming protein RCMkappa-CN (reduced and carboxymethylated kappa-casein) and thereby protect pheochromocytoma-12 cells from RCMkappa-CN amyloid-induced toxicity. We found that EGCG potently inhibits in vitro fibril formation byRCMkappa-CN [the IC50 for 50 uM RCMkappa-CN is 1 uM]. Biophysical studies reveal that EGCG prevents RCMkappa-CN fibril formation by stabilising RCMkappa-CN in its nativelike state rather than by redirecting its aggregation to the disordered, amorphous aggregation pathway. Thus, while it appears that EGCG is a generic inhibitor of amyloid-fibril formation, the mechanism by which it achieves this inhibition is specific to the target fibril-forming polypeptide. It is proposed that EGCG is directed to the amyloidogenic sheet-turn-sheet motif of monomeric RCMkappa-CN with high affinity by strong non-specific hydrophobic associations. Additional non-covalent pi-pi stacking interactions between the polyphenolic and aromatic residues common to the amyloidogenic sequence are also implicated
(-)-Epigallocatechin-3-gallate (EGCG) maintains k-casein in its pre-fibrillar state without redirecting its aggregation pathway
The polyphenol (-)-epigallocatechin-3-gallate (EGCG) has recently attracted much research interest in the field of protein-misfolding diseases because of its potent anti-amyloid activity against amyloid-beta, alpha-synuclein and huntingtin, the amyloid-fibril-forming proteins involved in Alzheimer\u27s, Parkinson\u27s and Huntington\u27s diseases, respectively. EGCG redirects the aggregation of these polypeptides to a disordered off-folding pathway that results in the formation of non-toxic amorphous aggregates. whether this anti-fibril activity is specific to these disease-related target proteins or ismore generic remains to be established. In addition, the mechanism by which EGCG exerts its effects, as with all anti-amyloidogenic polyphenols, remains unclear. To address these aspects, we have investigated the ability of EGCG to inhibit amyloidogenesis of the generic model fibril-forming protein RCMkappa-CN (reduced and carboxymethylated kappa-casein) and thereby protect pheochromocytoma-12 cells from RCMkappa-CN amyloid-induced toxicity. We found that EGCG potently inhibits in vitro fibril formation byRCMkappa-CN [the IC50 for 50 uM RCMkappa-CN is 1 uM]. Biophysical studies reveal that EGCG prevents RCMkappa-CN fibril formation by stabilising RCMkappa-CN in its nativelike state rather than by redirecting its aggregation to the disordered, amorphous aggregation pathway. Thus, while it appears that EGCG is a generic inhibitor of amyloid-fibril formation, the mechanism by which it achieves this inhibition is specific to the target fibril-forming polypeptide. It is proposed that EGCG is directed to the amyloidogenic sheet-turn-sheet motif of monomeric RCMkappa-CN with high affinity by strong non-specific hydrophobic associations. Additional non-covalent pi-pi stacking interactions between the polyphenolic and aromatic residues common to the amyloidogenic sequence are also implicated
- …