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

Risk analysis of COVID-19 hospitalization and critical care by race and region in the United States: a cohort study

Abstract Background This study aimed to identify the current risk factors for coronavirus disease 2019 severity and examine its association with medication use. Methods We used data from a large United States electronic health record database to conduct an anonymized cohort study of 171,491 patients with coronavirus disease 2019. The study was conducted from January 1, 2020, to August 27, 2021. Data on age, race, sex, history of diseases, and history of medication prescriptions were analyzed using the Cox proportional hazards model analysis to calculate hazard ratios for hospitalization and severe risk. Results Factors that increased the risk of hospitalization and critical care were age ≥ 65 years, male sex, type 2 diabetes, hypertension, interstitial pneumonia, and cardiovascular disease. In particular, age ≥ 65 years significantly increased the risk of hospitalization (hazard ratio, 2.81 [95% confidence interval, 2.58–3.07]; P < 0.001) and critical care (hazard ratio, 3.45 [2.88–4.14]; P < 0.001). In contrast, patients with hyperlipidemia had a reduced risk. However, patients with hyperlipidemia who were not taking statins had a significantly increased risk of hospitalization (hazard ratio, 1.24 [1.16–1.34]; P < 0.001). Sodium-glucose cotransporter-2 inhibitors, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, glucocorticoids, and statins significantly reduced the risk of hospitalization and critical care. The risk of hospitalization and critical care increased in patients of all ethnicities with type 2 diabetes. The factors that significantly increased the risk of hospitalization in all regions were older age, hypertension, chronic obstructive pulmonary disease, and cardiovascular disease. Conclusion This study identified factors that increase or reduce the risk of severe coronavirus disease. The provision of appropriate drug treatment and modification of lifestyle-related risk factors may reduce coronavirus disease severity

Asymmetric Alkylthienyl Thienoacenes Derived from Anthra[2,3‑<i>b</i>]thieno[2,3‑<i>d</i>]thiophene for Solution-Processable Organic Semiconductors

Anthra­[2,3-<i>b</i>]­thieno­[2,3-<i>d</i>]­thiophene (ATT), which is readily accessed from thieno­[3,2-<i>b</i>]­thiophene and 2,3-naphthalenedicarboxylic anhydride, allows for selective substitution at the terminal thiophene ring, thereby providing asymmetric monoalkyl and monoalkylthienyl thienoacenes. Alkyl-substituted ATT (CnATT, <i>n</i> = 6, 8, 10, 12) has characteristics of a p-type field-effect transistor (FET), with mobility on the order of 0.01 cm² V^–1 s^–1, which is the same as ATT. Conversely, alkylthienyl-substituted ATT (CnTATT, <i>n</i> = 6, 8, 10, 12) exhibits FET mobility of 0.15–1.9 cm² V^–1 s^–1, which is up to 2 orders of magnitude greater than that of ATT and CnATT. Moreover, CnTATT forms crystalline thin films both by spin coating and drop casting, and C8TATT in particular exhibits a mobility of up to 1.6 cm² V^–1 s^–1 in the drop-cast film. X-ray diffraction patterns of CnTATT thin films indicate that the molecules become oriented edge-on at the substrate surface with a highly ordered structure in the in-plane direction. Accordingly, CnTATT serves as a solution-processable p-type organic field-effect transistor, where the additional thiophene ring contributes significantly to the highly ordered thin-film structure and the high carrier mobility

Asymmetric Alkylthienyl Thienoacenes Derived from Anthra[2,3‑<i>b</i>]thieno[2,3‑<i>d</i>]thiophene for Solution-Processable Organic Semiconductors

Anthra­[2,3-<i>b</i>]­thieno­[2,3-<i>d</i>]­thiophene (ATT), which is readily accessed from thieno­[3,2-<i>b</i>]­thiophene and 2,3-naphthalenedicarboxylic anhydride, allows for selective substitution at the terminal thiophene ring, thereby providing asymmetric monoalkyl and monoalkylthienyl thienoacenes. Alkyl-substituted ATT (CnATT, <i>n</i> = 6, 8, 10, 12) has characteristics of a p-type field-effect transistor (FET), with mobility on the order of 0.01 cm² V^–1 s^–1, which is the same as ATT. Conversely, alkylthienyl-substituted ATT (CnTATT, <i>n</i> = 6, 8, 10, 12) exhibits FET mobility of 0.15–1.9 cm² V^–1 s^–1, which is up to 2 orders of magnitude greater than that of ATT and CnATT. Moreover, CnTATT forms crystalline thin films both by spin coating and drop casting, and C8TATT in particular exhibits a mobility of up to 1.6 cm² V^–1 s^–1 in the drop-cast film. X-ray diffraction patterns of CnTATT thin films indicate that the molecules become oriented edge-on at the substrate surface with a highly ordered structure in the in-plane direction. Accordingly, CnTATT serves as a solution-processable p-type organic field-effect transistor, where the additional thiophene ring contributes significantly to the highly ordered thin-film structure and the high carrier mobility