Notes

[Dynamics involving cognitive disabilities through L-dopa treatments throughout Parkinson's disease].
Smart coatings have aroused a growing interest because of the performance of predefined surface functions upon reacting to external stimuli. Among them, responsive polymer coatings to water, which often benefit from the presence of a mobile hydrophilic material, are of great interest. Polyurethanes (PUs) are versatile materials with respect to the structure-property relationship. Therefore, the incorporation of hydrophilic segments in PUs is a rational way to produce water-sensitive smart coatings; however, having a considerable amount of hydrophilic material deteriorates the physical properties because of a large amount of water uptake. In this study, we have analyzed previously synthesized smart PUs, based on hydrophobic polycarbonate (PC) and hydrophilic polyethylene glycol (PEG) soft segments, in which only a limited amount of PEG is used. These coatings maintain, more or less, zero water contact angle, whereas the water uptake remains below 15 wt %. The combination of experimental analysis and coarse-grained molecular dynamics (CG MD) simulations reveals that PEG segments migrate to the coating/water interface and partially cover the surface, whereas the hydrophobic nature of the PC keeps the bulk of the coating intact when the coating is covered with water. Moreover, our CG MD simulations and experimental analysis suggest a reversible phase arrangement under wet/dry cycles on molecular and macroscopic scales.Redoxmers are electrochemically active organic molecules storing charge and energy in electrolyte fluids circulating through redox flow batteries (RFBs). Such molecules typically have solvent-repelling cores and solvent-attracting pendant groups introduced to increase solubility in liquid electrolytes. These two features can facilitate nanoscale aggregation of the redoxmer molecules in crowded solutions. In some cases, this aggregation leads to the emergence of continuous networks of solute molecules in contact, and the solution becomes microscopically heterogeneous. Here, we use small-angle X-ray scattering (SAXS) and molecular dynamics modeling to demonstrate formation of such networks and examine structural factors controlling this self-assembly. We also show that salt ions become excluded from these solute aggregates into small pockets of electrolytes, where these ions strongly associate. This confinement by exclusion is also likely to occur to charged redoxmer molecules in a "sea" of neutral precursors coexisting in the same solution. Here, we demonstrate that the decay lifetime of the confined charged molecules in such solutions can increase several fold compared to dilute solutions. We attribute this behavior to a "microreactor effect" on reverse reactions of the confined species during their decomposition.Inhibiting the cytotoxicity of amyloid aggregation by endogenous proteins is a promising strategy against degenerative amyloid diseases due to their intrinsically high biocompatibility and low immunogenicity. In this study, we investigated the inhibition mechanism of the structured core region of αB-crystallin (αBC) against Aβ fibrillization using discrete molecular dynamics simulations. Our computational results recapitulated the experimentally observed Aβ binding sites in αBC and suggested that αBC could bind to various Aβ aggregate species during the aggregation process-including monomers, dimers, and likely other high molecular weight oligomers, protofibrils, and fibrils-by capping the exposed β-sheet elongation surfaces. Thus, the nucleation of Aβ oligomers into fibrils and the fibril growth could be inhibited. Mechanistic insights obtained from our systematic computational studies may aid in the development of novel therapeutic strategies to modulate the aggregation of pathological, amyloidogenic protein in degenerative diseases.The emergence in late 2019 of the coronavirus SARS-CoV-2 has resulted in the breakthrough of the COVID-19 pandemic that is presently affecting a growing number of countries. The development of the pandemic has also prompted an unprecedented effort of the scientific community to understand the molecular bases of the virus infection and to propose rational drug design strategies able to alleviate the serious COVID-19 morbidity. In this context, a strong synergy between the structural biophysics and molecular modeling and simulation communities has emerged, resolving at the atomistic level the crucial protein apparatus of the virus and revealing the dynamic aspects of key viral processes. In this Review, we focus on how in silico studies have contributed to the understanding of the SARS-CoV-2 infection mechanism and the proposal of novel and original agents to inhibit the viral key functioning. This Review deals with the SARS-CoV-2 spike protein, including the mode of action that this structural protein uses to entry human cells, as well as with nonstructural viral proteins, focusing the attention on the most studied proteases and also proposing alternative mechanisms involving some of its domains, such as the SARS unique domain. We demonstrate that molecular modeling and simulation represent an effective approach to gather information on key biological processes and thus guide rational molecular design strategies.Helicobacter pylori, the most common cause of chronic gastritis, peptic ulcers, and gastric cancers, infects around half of the world's population. Although the drawbacks of antibiotic-based combination therapy are emerging, no effective vaccine is available to prevent H. pylori infections. Here, we describe the total synthesis of the unique α-(1→3)-linked tri-d-glycero-d-manno-heptose antigen from the lipopolysaccharide of H. pylori serogroups O3 and O6 and strains MO19, D2, D4, and D5 based on de novo synthesis of the differentially protected d-glycero-d-manno-heptosyl building blocks. Immunization of mice with the semisynthetic glycoconjugate elicited a very robust T-cell-dependent antigen-specific immune response, resulting in very high titers of IgG1 and IgG2b protective antibody isotypes. The postimmune sera recognized H. pylori NCTC 11637 and bound strongly to the surface of the intact bacteria.Despite the remarkable reactivity that was achieved by a series of transition-metal catalysts with a PNP type ligand, the electron-rich chiral PNP ligands have still been rarely reported because of the difficulties in synthesis and the nature of air-sensitivity. Herein, we report a novel chiral PNP ligand (Heng-PNP) with both a rigid backbone and a bulky tert-butyl group on the phospholane motif. We successfully obtained its divalent iron complex. The chiral environment of its Ir(III) complex was also discussed with quadrant analysis. This tridentate ligand was applied in iridium-catalyzed asymmetric hydrogenation of challenging diaryl ketones up to 98% ee and 500 TON are achieved. Computational study showed that the twist of conjugate aryl group in the substrate (induced by the special chiral pocket of Ir/Heng-PNP complex) leads to the energy difference in the enantiodetermining step.Enzymatic suicide inactivation, a route of permanent enzyme inhibition, is the mechanism of action for a wide array of pharmaceuticals. Here, we developed the first nanosensor that selectively reports the suicide inactivation pathway of an enzyme. The sensor is based on modulation of the near-infrared fluorescence of an enzyme-bound carbon nanotube. The nanosensor responded selectively to substrate-mediated suicide inactivation of the tyrosinase enzyme via bathochromic shifting of the nanotube emission wavelength. Mechanistic investigations revealed that singlet oxygen generated by the suicide inactivation pathway induced the response. We used the nanosensor to quantify the degree of enzymatic inactivation by measuring response rates to small molecule tyrosinase modulators. This work resulted in a new capability of interrogating a specific route of enzymatic death. Angiotensin II human order Potential applications include drug screening and hit-validation for compounds that elicit or inhibit enzymatic inactivation and single-molecule measurements to assess population heterogeneity in enzyme activity.The magnetic coupling interaction of Mn2+-Mn2+ in Mn2+-included phosphors could induce a shorter emission decay time, compared with that of isolated Mn2+, which could overcome the photoluminescence (PL) saturation when stimulated by a high photon flux due to the long lifetime of the Mn2+ excited state. However, few studies have directly proved the Mn2+-Mn2+ coupling effect on the PL decay. In this paper, the effect on PL of CsMnCl3 (CMC) and its hydrates is revealed by photomagnetism results, excluding the interference effects of site symmetry and phonon energy. The antiferromagnetic interaction of the CMC is larger when Mn2+ at a photoexcited state than at a dark state, which is contrary to the hydrates with weak Mn2+-Mn2+ interaction. This research not only helps researchers to understand the fundamental optical process but also is instructive for designing high performance Mn2+-doped phosphors in the field of displays and lighting.Antimicrobial photodynamic therapy (APDT) is a promising alternative to traditional antibiotics for the treatment of bacterial infections, which inactivates a broad spectrum of bacteria. However, many traditional photosensitizers (PSs) are hydrophobic with poor water solubility and easy aggregation. On the other hand, some light sources such as ultraviolet (UV) have poor penetration and high cytotoxicity. Both issues lead to undesired photodynamic therapy efficacy. To overcome these issues, we develop a novel water-soluble natural PS (sorbicillinoids) obtained by microbial fermentation using recombinant filamentous fungus Trichoderma reesei. Sorbicillinoids could effectively generate singlet oxygen (1O2) under UV light irradiation and ultimately display photoinactivation activity on Gram-positive bacteria including Staphylococcus aureus, Bacillus subtilis, and Micrococcus luteus but not Gram-negative ones such as Escherichia coli and Proteus vulgaris. Sorbicillinoids were found to enter S. aureus but not E. coli. S. aureus treated with sorbicillinoids and UV light displayed high levels of intracellular reactive oxygen species (ROS), notable DNA photocleavage, and compromised cell semipermeability without overt cell membrane disruption, none of which was found in the treated E. coli. All these contribute to the sorbicillinoid-based photoinactivation of Gram-positive bacteria. Moreover, the dark toxicity and phototoxicity on mammalian cells or hemolysis activity of sorbicillinoids is negligible, showing its excellent biocompatibility. This study expands the utilization of UV light for surface sterilization to disinfection in solution. Therefore, sorbicillinoids, a type of secondary metabolite from fungus, have a promising future as a new PS for APDT using a nontoxic dose of UV irradiation.A novel concept that conversion of chiral 2-substituted DMAP into its DMAP-N-oxide could significantly enhance the catalytic activity and still be used as an acyl transfer catalyst is presented. A new type of chiral 2-substituted DMAP-N-oxides, derived from l-prolinamides, has been rationally designed, facilely synthesized, and applied in the dynamic kinetic resolution of azlactones. Using simple MeOH as the nucleophile, various l-amino acid derivatives were produced in high yields (up to 98% yield) and enantioselectivities (up to 96% ee). Furthermore, α-deuterium labeled l-phenylalanine derivative was also obtained. Experiments and DFT calculations revealed that in 2-substituted DMAP-N-oxide, the oxygen atom acted as the nucleophilic site and the N-H bond functioned as the H-bond donor. High enantioselectivity of the reaction was governed by steric factors, and the addition of benzoic acid reduced the activation energy by participating in the construction of a H-bond bridge. The theoretical chemical study indicated that only when attack directions of the chiral catalyst were fully considered could the correct calculation results be obtained.
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