Tetracycline and its Analogues as Drugs Against Protein Aggregation and Amyloid Formation

With more than 20 million cases worldwide, Alzheimer’s disease (AD) is now the most common neurodegenerative disease. The two defining features of this disease are extracellular plaques and intracellular neurofibrillary tangles. Although no AD treatment is available, researchers are making encouraging progress, including the use of small compounds which interact with amyloid-β (AB) and affect its self aggregation. Tetracyclines (TCs) are thought to have an anti-amyloidogenic effect on Aβ peptides. But the inconsistency of results in literature prompted us to further investigate the behaviour of various fragments of Aβ (Aβ1-40; Aβ1-42; guest-host-peptide Aβ 14-24) which were synthesised as depsi-peptides, in the presence of TCs. Due to their superior solubility the depsi-peptides allowed us to prepare reliable and seed-free stock solutions with reproducible properties. These allowed the preparation of different well-characterised Aβ1-42 species (initial state, oligomers, and fibrils), and to investigate the binding of Aβ ligands (Aβ monomers or TCs) to them or to study the modulation of the kinetics of fibril formation in the absence or presence of TCs, by Surface Plasmon Resonance (SPR), Circular Dichroism (CD) or Thioflavine-T (ThT) fluorescence. Binding of Aβ1-42 monomers to immobilised fibrils could be well described by the “Dock and Lock” mechanism. TCs do not bind to the prepared Aβ species nor do they alter the highly reproducible kinetics of fibril formation or disaggregated preformed amyloidogenic structures. Consistent with the inactivity of TCs against amyloid β-sheet structures the treatment of APP/PS1tg mice with doxycycline (DC) after plaque formation did not change the plaque load in this mouse model compared to the control mice. These findings suggest that toxic Ap species other than these considered in this study or the common neuroprotection seen for TCs might be responsible for the positive effects in-vivo in previously reported studies

Surface composition of AgPd single-atom alloy catalyst in an oxidative environment

Single-atom alloys (SAAs) have recently gained considerable attention in the field of heterogeneous catalysis research due to their potential for novel catalytic properties. While SAAs are often examined in reactions of reductive atmospheres, such as hydrogenation reactions, in the present work, we change the focus to AgPd SAAs in oxidative environments since Pd has the highest catalytic activity of all metals for oxidative reactions. Here, we examine how the chemical reactivity of AgPd SAAs differs from its constituent Pd in an oxidative atmosphere. For this purpose, electronic structure changes in an Ag0.98Pd0.02 SAA foil in 1 mbar of O2 were studied by in situ x-ray photoemission spectroscopy and compared with the electronic structure of a Pd foil under the same conditions. When heated in an oxidative atmosphere, Pd in Ag0.98Pd0.02 partly oxidizes and forms a metastable PdOx surface oxide. By using a peak area modeling procedure, we conclude that PdOx on Ag0.98Pd0.02 is present as thin, possibly monolayer thick, PdOx islands on the surface. In comparison to the PdO formed on the Pd foil, the PdOx formed on AgPd is substantially less thermodynamically stable, decomposing at temperatures about 270 °C lower than the native oxide on Pd. Such behavior is an interesting property of oxides formed on dilute alloys, which could be potentially utilized in catalytic oxidative reactions such as methane oxidation

Isolated Pd atoms in a silver matrix: Spectroscopic and chemical properties

Over the past decade, single-atom alloys (SAAs) have been a lively topic of research due to their potential for achieving novel catalytic properties and circumventing some known limitations of heterogeneous catalysts, such as scaling relationships. In researching SAAs, it is important to recognize experimental evidence of peculiarities in their electronic structure. When an isolated atom is embedded in a matrix of foreign atoms, it exhibits spectroscopic signatures that reflect its surrounding chemical environment. In the present work, using photoemission spectroscopy and computational chemistry, we discuss the experimental evidence from Ag0.98Pd0.02 SAAs that show free-atom-like characteristics in their electronic structure. In particular, the broad Pd4d valence band states of the bulk Pd metal become a narrow band in the alloy. The measured photoemission spectra were compared with the calculated photoemission signal of a free Pd atom in the gas phase with very good agreement, suggesting that the Pd4d states in the alloy exhibit very weak hybridization with their surroundings and are therefore electronically isolated. Since AgPd alloys are known for their superior performance in the industrially relevant semi-hydrogenation of acetylene, we considered whether it is worthwhile to drive the dilution of Pd in the inert Ag host to the single-atom level. We conclude that although site-isolation provides beneficial electronic structure changes to the Pd centers due to the difficulty in activating H2 on Ag, utilizing such SAAs in acetylene semi-hydrogenation would require either a higher Pd concentration to bring isolated sites sufficiently close together or an H2-activating support

Inelastic electron scattering by the gas phase in near ambient pressure XPS measurements

X‐ray photoemission spectroscopy (XPS) measurements in near‐ambient pressure (NAP) conditions result in a signal loss of the primary spectrum as a result of inelastic scattering of photoelectrons in the gas phase. The inelastic scattering of the primary electrons gives rise to a secondary signal that can result in additional and often unwanted features in the measured spectrum. In the present work, we derive equations that can be used to model the resulting signal and provide equations that can be used to simulate or remove the inelastic scattering signal from measured spectra. We demonstrate this process for photoemission spectra of a wide range of kinetic energies, measured from Au, Ag, and Cu, in a variety of gases (N2, He, H2, and O2). The work is supplemented with an open‐source software in which the algorithms described here have been implemented and can be used to remove the gas phase inelastic scattering signal

Inspección de Trabajo y Seguridad Social (caso práctico)

In this practical case is reproduced the statement of assumption refered to the activity of the Inspection of Labour and Social Security that was proposed as the second exercise in the competition for admission to the Higher Body of Inspectors of Labour and Social Security made by Order TIN/2339/2009 of August 4 –BOE of September 2–. It is an analysis of the issues arising from the planning, incorporating the legal basis of the response.En el presente caso práctico se reproduce el enunciado del supuesto referido a la actividad de la Inspección de Trabajo y Seguridad Social que se planteó como segundo ejercicio en la convocatoria de la oposición para el ingreso en el Cuerpo Superior de Inspectores de Trabajo y Seguridad Social efectuada por Orden TIN/2339/2009, de 4 de agosto –BOE de 2 de septiembre–. En él se efectúa un análisis de las cuestiones derivadas del planteamiento, incorporando la fundamentación jurídica de la respuesta

Can Antiviral Activity of Licorice Help Fight COVID-19 Infection?

peer reviewedThe phytotherapeutic properties of Glycyrrhiza glabra (licorice) extract are mainly attributed to glycyrrhizin (GR) and glycyrrhetinic acid (GA). Among their possible pharmacological actions, the ability to act against viruses belonging to different families, including SARS coronavirus, is particularly important. With the COVID-19 emergency and the urgent need for compounds to counteract the pandemic, the antiviral properties of GR and GA, as pure substances or as components of licorice extract, attracted attention in the last year and supported the launch of two clinical trials. In silico docking studies reported that GR and GA may directly interact with the key players in viral internalization and replication such as angiotensin-converting enzyme 2 (ACE2), spike protein, the host transmembrane serine protease 2, and 3-chymotrypsin-like cysteine protease. In vitro data indicated that GR can interfere with virus entry by directly interacting with ACE2 and spike, with a nonspecific effect on cell and viral membranes. Additional anti-inflammatory and antioxidant effects of GR cannot be excluded. These multiple activities of GR and licorice extract are critically re-assessed in this review, and their possible role against the spread of the SARS-CoV-2 and the features of COVID-19 disease is discussed

Phase coexistence of multiple copper oxides on AgCu catalysts during ethylene epoxidation

Alloy catalysts under reaction conditions are complex entities. In oxidizing atmospheres, multiple phases can coexist on a catalyst s surface as a result of phase segregation and preferential oxidation. Such a scenario can result in unusual substoichiometric and metastable phases that could play important roles in catalytic processes. For instance, AgCu alloys known to exhibit enhanced epoxide selectivity in partial oxidation of ethylene form an oxide like surface structure under reaction conditions. Under these conditions, copper oxides are stable, while silver oxides are not. Consequently, copper segregates to the alloy s surface and forms an oxide overlayer. Little is known about the structure or function of such overlayers, and it is unknown whether they play an active role in the catalyst s enhanced selectivity. In order to develop a clearer picture of such catalysts, the current work utilizes several in situ spectroscopic and microscopic techniques to examine the copper oxide phases that form when AgCu is exposed to epoxidation conditions. It is found that several forms of oxidic Cu coexist simultaneously on the active catalyst s surface, namely, CuO, Cu2O, and some previously unreported form of oxidized Cu, referred to here as CuxOy. Online product analysis, performed during the in situ spectroscopic measurements, shows that increased epoxide selectivity is correlated with the presence of mixed copper oxidation states and the presence of the CuxOy species. These results support previous theoretical predictions that oxidic copper overlayers on silver play an active role in epoxidation. These results furthermore emphasize the need for in situ spectromicroscopic methods to understand the complexity of alloy catalyst

Kinesin's backsteps under mechanical load

Kinesins move processively toward the plus end of microtubules by hydrolyzing ATP for each step. From an enzymatic perspective, the mechanism of mechanical motion coupled to the nucleotide chemistry is often well explained using a single-loop cyclic reaction. However, several difficulties arise in interpreting kinesin's backstepping within this framework, especially when external forces oppose the motion of kinesin. We review evidence, such as an ATP-independent stall force and a slower cycle time for backsteps, that has emerged to challenge the idea that kinesin backstepping is due to ATP synthesis, i.e., the reverse cycle of kinesin's forward-stepping chemomechanics. Supplementing the conventional single-loop chemomechanics with routes for ATP-hydrolyzing backward steps and nucleotide-free steps, especially under load, gives a better physical interpretation of the experimental data on backsteps.Comment: 5 figures and 2 table