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Objective: The most common pathogenesis for familial Alzheimer's disease (FAD) involves misprocessing (or alternative processing) of the amyloid precursor protein (APP) by γ-secretase due to mutations of the presenilin 1 (PS1) gene. This misprocessing/alternative processing leads to an increase in the ratio of the level of a minor γ-secretase reaction product (Aβ42) to that of the major reaction product (Aβ40). Although no PS1 mutations are present, altered Aβ42/40 ratios are also observed in sporadic Alzheimer's disease (SAD), and these altered ratios apparently reflect deposition of Aβ42 as amyloid.Methods: Using immunoprecipitation-mass spectrometry with quantitative accuracy, we analyzed in the cerebrospinal fluid (CSF) of various clinical populations the peptide products generated by processing of not only APP but also an unrelated protein, alcadein (Alc). Alc undergoes metabolism by the identical APP α-secretases and γ-secretases, yielding a fragment that we have named p3-Alc(α) because of the parallel genesis of p3-Alc(α) peptides and the p3 fragment of APP. As with Aβ, both major and minor p3-Alc(α) s are generated. We studied the alternative processing of p3-Alc(α) in various clinical populations.Results: We previously reported that changes in the Aβ42/40 ratio showed covariance in a linear relationship with the levels of p3-Alc(α) [minor/major] ratio in media conditioned by cells expressing FAD-linked PS1 mutants. Here we studied the speciation of p3-Alc(α) in the CSF from 3 groups of human subjects (n = 158): elderly nondemented control subjects; mild cognitive impairment (MCI) subjects with a clinical dementia rating (CDR) of 0.5; SAD subjects with CDR of 1.0; and other neurological disease (OND) control subjects. The CSF minor p3-Alc(α) variant, p3-Alc(α) 38, was elevated (p < 0.05) in MCI subjects or SAD subjects, depending upon whether the data were pooled and analyzed as a single cohort or analyzed individually as 3 separate cohorts.Interpretation: These results suggest that some SAD may involve alternative processing of multiple γ-secretase substrates, raising the possibility that the molecular pathogenesis of SAD might involve γ-secretase dysfunction. [ABSTRACT FROM AUTHOR]

Some patients with developmental and epileptic encephalopathy (DEE) respond to adrenocorticotropic hormone (ACTH) therapy but relapse soon after. While long-term ACTH therapy (LT-ACTH) has been attempted for these patients, no previous studies have carefully assessed adrenal function during LT-ACTH. We evaluated the effectiveness of LT-ACTH, as well as adverse effects (AE), including their adrenal function in three DEE patients. Patients underwent a corticotropin-releasing hormone (CRH) stimulation test during LT-ACTH, and those with peak serum cortisol below 15 μg/dL were considered to be at high risk of adrenal insufficiency (AI). Two of three responded, and their life-threatening seizures with postgeneralized electroencephalogram (EEG) suppression decreased. Although no individuals had serious AE, CRH stimulation test revealed relatively weak responses, without reaching normal cortisol peak level (18 μg/dL). Hydrocortisone replacement during stress was prepared in a case with lower cortisol peak than our cutoff level. LT-ACTH could be a promising treatment option for cases of DEE that relapse soon after effective ACTH treatment. The longer duration and larger cumulative dosage in LT-ACTH than in conventional ACTH could increase the relative risk of AI. Careful evaluation with pediatric endocrinologists, including hormonal stimulation tests, might be useful for continuing this treatment safely., (© 2021 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

The three-dimensional reference interaction-site model self-consistent-field (3D-RISM-SCF) method was applied to the electronic structure of hexahydrated chromium trication [Cr(H2O)6](3+) in aqueous solution. The 3D distribution around [Cr(H2O)6](3+) showed 12 maximum density points arising from hydrogen bonds, as well as eight local maximum points at the hollow sites, in the second hydration shell. The 3D distribution function also indicated 20 local maximum sites in the third hydration shell. The low-lying excited states of vertical transitions were computed using time-dependent density functional theory (TD-DFT), including the electric field from the solvent. The electronic configurations and excitation energies calculated using DFT and 3D-RISM-SCF were very similar, although the orbital energies involved in the transition were rather different. The two lowest excited states (1(4)T and 2(4)T) were roughly assigned to the d-d transitions, and the third and fourth excited states (3(4)T and 4(4)T) were assigned to ligand-to-metal charge-transfer transitions. The computed excited energies were in good agreement with the experimental values.

The synthesis, structures, optical and redox properties, and reactivity of phosphaporphyrins are reported. The 21-phosphaporphyrin (P,N(3)-porphyrin) and 23-phospha-21-thiaporphyrin (P,S,N(2)-porphyrin) were prepared via acid-promoted dehydrative condensation between a phosphatripyrrane and the corresponding 2,5-bis[hydroxy(phenyl)methyl]heteroles followed by 2,3-dichloro-5,6-dicyanobenzoquinone oxidation. Experimental (NMR, UV-vis, and X-ray analyses) and theoretical (DFT calculations) results suggest that the 18pi aromaticity inherent in regular N(4)-porphyrins was maintained in these phosphaporphyrins. X-ray crystallography revealed a slightly distorted 18pi aromatic ring for the P,N(3)-porphyrin with the phosphole and three pyrrole rings tilted from the 24-atoms mean plane by 9.6 degrees and 3.8-15.4 degrees, respectively. DFT calculations on model compounds showed that the P,X,N(2)-porphyrins (X = N, S) possess considerably small HOMO-LUMO gaps as compared with N(4)- and S,N(3)-porphyrins, which is reflected in the red-shifted absorptions, low oxidation potentials, and high reduction potentials of the phosphaporphyrins. The P-oxygenation of the P,X,N(2)-porphyrins with H(2)O(2) has been found to lead to the formation of different types of products. The 18pi P,N(3)-porphyrin was transformed into the 22pi aromatic P(O),N(3)-porphyrin accompanied by the pi extension at the peripheral C(3) bridge, whereas the 18pi P,S,N(2)-porphyrin was converted to the isophlorin-type 20pi antiaromatic P(O),S,N(2)-porphyrin. In both of the reactions, simple P-oxygenated 18pi P(O),X,N(2)-porphyrins were formed as the initial products, which were subsequently transformed into the 22pi or 20pi porphyrins. The two reaction courses from 18pi to 20pi/22pi are apparently determined by the combination of the core heteroatoms (i.e., P,N(3) or P,S,N(2)) and the structure of the peripherally fused carbocycles. The present results demonstrate that the incorporation of a phosphorus atom into the core is not only a highly promising way to modify the fundamental properties of the porphyrin 18pi system but also a reliable tool to stabilize uncommon 22pi and 20pi systems through the chemical modifications at the core phosphorus atom.

Alcadeins (Alcs) constitute a family of neuronal type I membrane proteins, designated Alc(alpha), Alc(beta), and Alc(gamma). The Alcs express in neurons dominantly and largely colocalize with the Alzheimer amyloid precursor protein (APP) in the brain. Alcs and APP show an identical function as a cargo receptor of kinesin-1. Moreover, proteolytic processing of Alc proteins appears highly similar to that of APP. We found that APP alpha-secretases ADAM 10 and ADAM 17 primarily cleave Alc proteins and trigger the subsequent secondary intramembranous cleavage of Alc C-terminal fragments by a presenilin-dependent gamma-secretase complex, thereby generating "APP p3-like" and non-aggregative Alc peptides (p3-Alcs). We determined the complete amino acid sequence of p3-Alc(alpha), p3-Alc(beta), and p3-Alc(gamma), whose major species comprise 35, 37, and 31 amino acids, respectively, in human cerebrospinal fluid. We demonstrate here that variant p3-Alc C termini are modulated by FAD-linked presenilin 1 mutations increasing minor beta-amyloid species Abeta42, and these mutations alter the level of minor p3-Alc species. However, the magnitudes of C-terminal alteration of p3-Alc(alpha), p3-Alc(beta), and p3-Alc(gamma) were not equivalent, suggesting that one type of gamma-secretase dysfunction does not appear in the phenotype equivalently in the cleavage of type I membrane proteins. Because these C-terminal alterations are detectable in human cerebrospinal fluid, the use of a substrate panel, including Alcs and APP, may be effective to detect gamma-secretase dysfunction in the prepathogenic state of Alzheimer disease subjects.

The 18pi-sigma3- and 22pi-sigma4-phosphaporphyrins were successfully prepared by an acid-promoted condensation between a phosphatripyrrane and a 2,5-bis[hydroxy(phenyl)methyl]pyrrole, and their structures, aromaticity, and optical and electrochemical properties were disclosed. Notably, a sigma4-phosphaporphyrinogen and the 18pi-sigma3-phosphaporphyrin undergo oxidative pi-extension at the peripherally fused carbocycle to afford the 22pi-sigma4-phosphaporphyrin.

There is an urgent need to develop an efficient technique to remove urea from the blood or gastrointestinal tract of uremic patients. Activated charcoals have a low sorption capacity for urea although they effectively remove other uremic toxic substances. To provide an urea-reactive adsorbent, a chemically modified oxystarch with albumin or gelatin has been prepared. Elemental analysis and Fourier transform infrared (FT-IR) spectroscopic analysis demonstrate that the reaction of a small amount of protein (albumin or gelatin) with oxystarch has taken place possibly by chemical combination. The influence of the dialdehyde content of the oxystarch on urea sorption, its sorption isotherm, and the adsorption rates have been investigated. It was found that the swelling factor of the oxystarch is closely related to the sorption activity under physiological conditions (pH 7.2-7.4 at 37 degrees C). Adsorption studies have shown that sorption capacity is increased by surface treatment and can reach 6-8.2 g urea/kg-dried adsorbent (initial urea concentration was 70 mg/dL). The oxystarch had 49.2% of glucose unit oxidized and was surface treated with albumin. These results suggest that the newly prepared surface-treated oxystarch would be utilized as an effective chemisorbent for urea removal under physiological conditions.