Leuco Ethyl Violet as Self-Activating Prodrug Photocatalyst for In Vivo Amyloid-Selective Oxygenation.

Aberrant aggregates of amyloid-ß (Aß) and tau protein (tau), called amyloid, are related to the etiology of Alzheimer disease (AD). Reducing amyloid levels in AD patients is a potentially effective approach to the treatment of AD. The selective degradation of amyloids via small molecule-catalyzed photooxygenation in vivo is a leading approach; however, moderate catalyst activity and the side effects of scalp injury are problematic in prior studies using AD model mice. Here, leuco ethyl violet (LEV) is identified as a highly active, amyloid-selective, and blood-brain barrier (BBB)-permeable photooxygenation catalyst that circumvents all of these problems. LEV is a redox-sensitive, self-activating prodrug catalyst; self-oxidation of LEV through a hydrogen atom transfer process under photoirradiation produces catalytically active ethyl violet (EV) in the presence of amyloid. LEV effectively oxygenates human Aß and tau, suggesting the feasibility for applications in humans. Furthermore, a concept of using a hydrogen atom as a caging group of a reactive catalyst functional in vivo is postulated. The minimal size of the hydrogen caging group is especially useful for catalyst delivery to the brain through BBB.

Quantitative Assays for Catalytic Photo-Oxygenation of Alzheimer Disease-Related Tau Proteins.

Catalytic photo-oxygenation of tau amyloid is a potential therapeutic approach to tauopathies, including Alzheimer disease (AD). However, tau is a complex target containing great molecular size and heterogeneous isoforms/proteoforms. Although catalytic photo-oxygenation has been confirmed when using catalyst 1 and recombinant tau pretreated with heparin, its effects on tau from human patients have not yet been clarified. In this study, focusing on the histidine residues being oxygenated, we have constructed two assay systems capable of quantitatively evaluating the catalytic activity when used on human patient tau: (1) fluorescence labeling at oxygenated histidine sites and (2) LC-MS/MS analysis of histidine-containing fragments. Using these assays, we identified 2 as a promising catalyst for oxygenation of human tau. In addition, our results suggest that aggregated tau induced by heparin is different from actual AD patient tau in developing effective photo-oxygenation catalysts.

Rugby Players Exhibit Stiffer Biceps Femoris, Lower Biceps Femoris Fascicle Length to Knee Extensors, and Knee Flexors to Extensors Muscle Volume Ratios Than Active Controls.

PURPOSE: This study aimed to determine if hamstring-strain-injury risk factors related to muscle structure and morphology differed between rugby union players and controls. METHODS: The biceps femoris long head (BFlh) fascicle length and passive muscle stiffness and relative and absolute muscle volume of knee flexors (KF) and extensors (KE) were measured in 21 male subelite rugby players and 21 male physically active nonathletes. RESULTS: BFlh fascicle length was significantly longer (mean difference [MD] = 1.6 [1.7] cm) and BFlh passive muscle stiffness was significantly higher in rugby players (MD = 7.8 [14.8] kPa). The absolute BFlh (MD = 71.9 [73.3] cm3), KF (MD = 332.3 [337.2] cm3), and KE (MD = 956.3 [557.4] cm3) muscle volumes were also significantly higher in rugby players. There were no significant differences in the relative BFlh and KF muscle volumes. The relative KE muscle volumes were significantly higher in rugby players (MD = 2.3 [3.7] cm3/kg). However, the percentage BFlh fascicle length:KE (MD = -0.1% [0.1%]), BFlh/KE (MD = -0.9% [1.9%]), and KF:KE (MD = -4.9% [5.9%]) muscle volume ratios were significantly lower in the rugby players. BFlh muscle volume significantly correlated with BFlh fascicle length (r = .59, r2 = .35) and passive muscle stiffness (r = .46, r2 = .21). CONCLUSION: Future prospective studies should examine whether there are threshold values in BFlh passive muscle stiffness and BFlh fascicle length:KE, BFlh:KE, and KF:KE muscle volume ratios for predicting hamstring strain injuries.

Catalytic photooxygenation degrades brain Aß in vivo.

Protein degradation induced by small molecules by recruiting endogenous protein degradation systems, such as ubiquitin-proteasome systems, to disease-related proteins is an emerging concept to inhibit the function of undruggable proteins. Protein targets without reliable ligands and/or existing outside the cells where ubiquitin-proteasome systems do not exist, however, are beyond the scope of currently available protein degradation strategies. Here, we disclose photooxygenation catalyst 7 that permeates the blood-brain barrier and selectively and directly degrades an extracellular Alzheimer's disease-related undruggable protein, amyloid-ß protein (Aß). Key was the identification of a compact but orange color visible light-activatable chemical catalyst whose activity can be switched on/off according to its molecular mobility, thereby ensuring high selectivity for aggregated Aß. Chemical catalyst-promoted protein degradation can be applied universally for attenuating extracellular amyloids and various pathogenic proteins and is thus a new entry to induced protein degradation strategies.

High-Pressure Synthesis and Crystal Structure of the Sulfur-Richest Chromium Sulfide CrS3 Composed of Cr(III) and Disulfide Ions.

The new binary chromium sulfide CrS3 has been synthesized by reaction of Cr3S4 and sulfur mixtures at 800 °C and 13 GPa. CrS3 crystallizes in an orthorhombic unit cell with a = 4.6742(7) Å, b = 5.7315(8) Å, c = 10.603(2) Å, and V = 284.873(4) Å3. It has a novel structure composed of Cr2S10 edge-shared octahedral dimers, which share all of their corners to form a three-dimensional structure. All of the sulfur atoms form S22- disulfide ions with a S-S distance of 2.063(5) or 2.068(8) Å. The structure of CrS3 is a derivative of the crystal structure of marcasite FeS2, in which one in three metal sites of the marcasite structure is vacant in the CrS3 structure.

Kinetic analyses and structure-activity relationship studies of synthetic lysine acetylation catalysts.

Lysine acylation of proteins is a crucial chemical reaction, both as a post-translational modification and as a method for bioconjugation. We previously developed a chemical catalyst, DSH, which activates a chemically stable thioester including acyl-CoA, allowing the site-selective lysine acylation of histones under physiological conditions. However, a more active catalyst is required for efficient lysine acylation in more complex biological milieu, such as in living cells, but there are no rational guidelines for developing efficient lysine acylation catalysts for use under physiological conditions as opposed to in organic solvents. We, herein, conducted a kinetic analysis of the ability of DSH and several derivatives to mediate lysine acetylation to better understand the structural elements essential for high acetylation activity under physiological conditions. Interestingly, the obtained trend in reactivity was different from that observed in organic solvents, suggesting that a different principle is necessary for designing chemical catalysts specifically for use under physiological conditions compared to catalysts for use in organic solvents. Based on the obtained information, we identified a new catalyst scaffold with high activity and structural flexibility for further modification to improve this catalyst system.

Optical properties of fluoride thin films deposited by RF magnetron sputtering.

Fluoride thin films for 193-nm lithography were deposited by three different types of RF magnetron sputtering. Systematic analysis of the relation between optical properties and deposition conditions of these thin films is discussed.