Effect of Phosphatidylserine and Cholesterol on Membrane-mediated Fibril Formation by the N-terminal Amyloidogenic Fragment of Apolipoprotein A-I

Here, we examined the effects of phosphatidylserine (PS) and cholesterol on the fibril-forming properties of the N-terminal 1‒83 fragment of an amyloidogenic G26R variant of apoA-I bound to small unilamellar vesicles. A thioflavin T fluorescence assay together with microscopic observations showed that PS significantly retards the nucleation step in fibril formation by apoA-I 1‒83/G26R, whereas cholesterol slightly enhances fibril formation. Circular dichroism analyses demonstrated that PS facilitates a structural transition from random coil to α-helix in apoA-I 1‒83/G26R with great stabilization of the α-helical structure upon lipid binding. Isothermal titration calorimetry measurements revealed that PS induces a marked increase in capacity for binding of apoA-I 1‒83/G26R to the membrane surface, perhaps due to electrostatic interactions of positively charged amino acids in apoA-I with PS. Such effects of PS to enhance lipid interactions and inhibit fibril formation of apoA-I were also observed for the amyloidogenic region-containing apoA-I 8‒33/G26R peptide. Fluorescence measurements using environment-sensitive probes indicated that PS induces a more solvent-exposed, membrane-bound conformation in the amyloidogenic region of apoA-I without affecting membrane fluidity. Since cell membranes have highly heterogeneous lipid compositions, our findings may provide a molecular basis for the preferential deposition of apoA-I amyloid fibrils in tissues and organs

Factors Associated with an Increase in On-Site Time of Pediatric Trauma Patients in a Prehospital Setting: A Nationwide Observational Study in Japan

The factors that prolong the on-site time in pediatric trauma cases in a prehospital setting are unknown. We investigated these factors using a national trauma registry in Japan. We identified pediatric trauma patients aged ≤18 years, from January 2004 to May 2019. We categorized cases into shorter (≤13 min) and longer (>13 min) prehospital on-site time groups. We performed multivariable logistic regression analysis with multiple imputations to assess the factors associated with longer prehospital on-site time. Overall, 14,535 patients qualified for inclusion. The median prehospital on-site time was 13 min. In the multivariable logistic regression analysis, the longer prehospital on-site time was associated with higher age; suicide (Odds ratio [OR] 1.27; 95% confidence interval [CI] 1.03–1.57); violence (OR 1.74; 95%CI 1.27–2.38); higher revised trauma score, abbreviated injury scale > 3 in the spine (OR 1.25; 95%CI 1.04–1.50), upper extremity (OR 1.26; 95%CI 1.11–1.44), and lower extremity (OR 1.25; 95%CI 1.14–1.37); immobilization (OR 1.16; 95%CI 1.06–1.27); and comorbid mental retardation (OR 1.56; 95%CI 1.11–2.18). In light of these factors, time in the field could be reduced by having more pediatric emergency physicians and orthopedic surgeons available

The extreme N-terminal region of human apolipoprotein A-I has a strong propensity to form amyloid fibrils

AbstractThe N-terminal 1–83 residues of apolipoprotein A-I (apoA-I) have a strong propensity to form amyloid fibrils, in which the 46–59 segment was reported to aggregate to form amyloid-like fibrils. In this study, we demonstrated that a fragment peptide comprising the extreme N-terminal 1–43 residues strongly forms amyloid fibrils with a transition to β-sheet-rich structure, and that the G26R point mutation enhances the fibril formation of this segment. Our results suggest that in addition to the 46–59 segment, the extreme N-terminal region plays a crucial role in the development of amyloid fibrils by the N-terminal fragment of amyloidogenic apoA-I variants

Two new triterpenoids from the roots of <i>Pinus densiflora</i>

<p>Chemical investigation of the roots of <i>Pinus densiflora</i> led to the isolation of two new triterpenoids, (24<i>S</i>)-3<i>β</i>-methoxy-24,25-epoxy-lanost-9(11)-ene (1) and 29-acetoxy-3<i>α</i>-methoxyserrat-14-en-21<i>α</i>-ol (2), together with three known serratene-type triterpenoids (3–5) and four known diterpenoids (6–9). Their structures were determined by spectroscopic analyses.</p