Meta-Analysis of APP Expression Modulated by SARS-CoV-2 Infection via the ACE2 Receptor

Alzheimer’s disease (AD) is characterized by the deposition of amyloid-beta (Aβ) plaques from improper amyloid-beta precursor protein (APP) cleavage. Following studies of inflammation caused by coronavirus-2019 (COVID-19) infection, this study investigated the impact of COVID-19 on APP expression. A meta-analysis was conducted utilizing QIAGEN Ingenuity Pathway Analysis (IPA) to examine the link between severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) and the modulation of APP expression upon virus binding the Angiotensin-converting enzyme-2 (ACE2) receptor. A Core Analysis was run on the infection by severe acute respiratory syndrome (SARS) coronavirus node, which included molecules affected by SARS-CoV-2, revealing its upstream regulators. Intermediary molecules were found between the upstream regulators and ACE2 and between ACE2 and APP. Activation of the upstream regulators downregulated the expression of ACE2 with a Z-score of −1.719 (p-value = 0.086) and upregulated APP with a Z-score of 1.898 (p-value = 0.058), showing a less than 10% chance of the results occurring by chance and pointing to an inverse relationship between ACE2 and APP expression. The neuroinflammation signaling pathway was the fifth top canonical pathway involved in APP upregulation. The study results suggest that ACE2 could be downregulated by SARS-CoV-2, resulting in APP upregulation, and potentially exacerbating the onset and progression of AD.     

Stereocontrolled Synthesis of Spiroketals: An Engine for Chemical and Biological Discovery

Spiroketals are key structural motifs found in diverse natural products with compelling biological activities. However, stereocontrolled synthetic access to spiroketals, independent of their inherent thermodynamic preferences, is a classical challenge in organic synthesis that has limited in-depth biological exploration of this intriguing class. Herein, we review our laboratory's efforts to advance the glycal epoxide approach to the stereocontrolled synthesis of spiroketals via kinetically controlled spirocyclization reactions. This work has provided new synthetic methodologies with applications in both diversity- and target-oriented synthesis, fundamental insights into structure and reactivity, and efficient access to spiroketal libraries and natural products for biological evaluation.     

Benzyl and naphthalene methylphosphonic acid inhibitors of autotaxin with anti-invasive and anti-metastatic activity

Autotaxin (ATX, NPP2) is a member of the nucleotide pyrophosphate phosphodiesterase enzyme family. ATX catalyzes the hydrolytic cleavage of lysophosphatidylcholine (LPC) by lysophospholipase D activity, which leads to generation of the growth‐factor‐like lipid mediator lysophosphatidic acid (LPA). ATX is highly upregulated in metastatic and chemotherapy‐resistant carcinomas and represents a potential target to mediate cancer invasion and metastasis. Herein we report the synthesis and pharmacological characterization of ATX inhibitors based on the 4‐tetradecanoylaminobenzylphosphonic acid scaffold, which was previously found to lack sufficient stability in cellular systems. The new 4‐substituted benzylphosphonic acid and 6‐substituted naphthalen‐2‐ylmethylphosphonic acid analogues block ATX activity with K_i values in the low micromolar to nanomolar range against FS3, LPC, and nucleotide substrates through a mixed‐mode inhibition mechanism. None of the compounds tested inhibit the activity of related enzymes (NPP6 and NPP7). In addition, the compounds were evaluated as agonists or antagonists of seven LPA receptor (LPAR) subtypes. Analogues 22 and 30 b , the two most potent ATX inhibitors, inhibit the invasion of MM1 hepatoma cells across murine mesothelial and human vascular endothelial monolayers in vitro in a dose‐dependent manner. The average terminal half‐life for compound 22 is 10±5.4 h and it causes a long‐lasting decrease in plasma LPA levels. Compounds 22 and 30 b significantly decrease lung metastasis of B16‐F10 syngeneic mouse melanoma in a post‐inoculation treatment paradigm. The 4‐substituted benzylphosphonic acids and 6‐substituted naphthalen‐2‐ylmethylphosphonic acids described herein represent new lead compounds that effectively inhibit the ATX–LPA–LPAR axis both in vitro and in vivo.     

Modifications of spider silk sequences in an attempt to control the mechanical properties of the synthetic fibers

Bacteria were genetically engineered to produce two spider silk protein variants composed of basic repeat units combining a flagelliform elastic motif ([GPGGX]₄) and a major ampullate silk strength motif ([linker/poly-alanine]. The secondary structures of the pure recombinant proteins in solution were determined by circular dichroism. The data presented suggest that the nature of the 5th and 10th amino acid (X) in the [GPGGX]₂ elastic motif and temperature have an impact on the amount of β-sheet structures present in the proteins. More specifically, increasing temperatures seem to be positively correlated with β-sheet formation for both proteins and this state is irreversible or reversible when both X (5th and 10th) in the elastic motif are hydrophilic or hydrophobic respectively. Moreover, each pure silk-like protein was able to spontaneously self-assemble into films from aqueous solutions. Two kinds of synthetic fibers were made by pulling fibers from these preassembled films as well as spinning fibers from each protein resolubilized in HFIP. The mechanical data show that the pulled fibers are far tougher than the spun fibers suggesting a better fiber organization. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Effect of pH on the Binding of Sodium,Lysine, and Arginine Counterions to <Emphasis Type="SmallCaps">l</Emphasis>-Undecyl Leucinate Micelles

Micelle formation by the amino acid-based surfactant undecylenyl l-leucine was investigated as a function of solution pH with NMR, dynamic light scattering, and fluorescence spectroscopy. NMR and dynamic light scattering showed that 50 mM undecylenyl l-leucine and 50 mM NaHCO₃ solutions contained micelles approximately 20 Å in diameter and that micelle radius and the mole fraction of surfactant molecules associated with micelles changed very little with solution pH. The binding of the amino acids arginine and lysine to the anionic micelles was also investigated from pH 7.0 to 11.5. Below pH 9.0, the mole fraction of arginine cations bound to the micelles was approximately 0.4. Above pH 9.0, the arginine counterions became zwitterionic, and the mole fraction of bound arginine molecules decreased steadily to less than 0.1 at pH 11. When arginine dissociated from the micelles, their radii decreased from 14 to 10 Å. Similar behavior was observed with lysine; however, when lysine dissociated from the micelle surface, little change in micelle radius was observed. Two-dimensional NMR experiments suggested that below pH 9.0, l-arginine bound perpendicular to the micelle surface primarily though its side chain amine while l-lysine bound parallel to the surface through both of its amine functional groups. Finally, the rate at which the amide protons on the surfactant headgoup exchanged with solvent was investigated with NMR spectroscopy. The exchange reaction was faster in solutions containing only surfactant monomers and slower when the surfactants were in micellar form and the headgoup amide protons were less exposed to solvent.     

Exploring the within-person coupling of sleep and cognition in older African Americans.

This study examined the within-person relationship between sleep and cognitive functioning. Fifty community-dwelling African Americans (age range = 50–80 years) were asked to report their sleep duration and quality the previous evening and to complete cognitive measures over 8 occasions within a 2–3 week period. A within-person daily change in sleep duration was significantly associated with worse global cognitive performance. The greater an individual deviated away from his or her average sleep duration on a particular day, the more likely his or her performance would decline. These results demonstrate that the sleep-cognition relationship can be observed at a within-person level of analysis. (PsycINFO Database Record (c) 2010 APA, all rights reserved)