New Kazhdan Groups

The group of simplicial automorphisms of a Tits–Kac–Moody infinite building of thickness q associated to a cocompact reflexion group with fundamental domain a simplex, is Kazhdan for q sufficiently large. Thus we obtain families of new Kazhdan groups: two in dimension 3 and one in dimension 4. The proof uses continuous cohomology, in particular a lemma of Casselman–Wigner, and Garland's vanishing method.     

On-Surface Synthesis and Determination of the Open-Shell Singlet Ground State of Tridecacene**

The character of the electronic structure of acenes has been the subject of longstanding discussion. However, convincing experimental evidence of their open-shell character has so far been missing. Here, we present the on-surface synthesis of tridecacene molecules by thermal annealing of octahydrotridecacene on a Au(111) surface. We characterized the electronic structure of the tridecacene by scanning probe microscopy, which reveals the presence of an inelastic signal at 126 meV. We attribute the inelastic signal to spin excitation from the singlet diradical ground state to the triplet excited state. To rationalize the experimental findings, we carried out many-body ab initio calculations as well as model Hamiltonians to take into account the effect of the metallic substrate. Moreover, we provide a detailed analysis of how the dynamic electron correlation and virtual charge fluctuation between the molecule and metallic surface reduces the singlet-triplet band gap. Thus, this work provides the first experimental confirmation of the magnetic character of tridecacene.     

Is Phytomelatonin Complex Better Than Synthetic Melatonin? The Assessment of the Antiradical and Anti-Inflammatory Properties

This work aims to assess the recently established anti-inflammatory and antioxidant potential of melatonin of plant origin extracted from the plant matrix as a phytomelatonin complex (PHT-MLT), and compare its activity with synthetic melatonin (SNT-MLT) when used on its own or with vitamin C. For this purpose, a COX-2 enzyme inhibitory activity test, an antiradical activity in vitro and on cell lines assays, was performed on both PHT-MLT and SNT-MLT products. COX-2 inhibitory activity of PHT-MLT was found to be ca. 6.5 times stronger than that of SNT-MLT (43.3% and 6.7% enzyme inhibition, equivalent to the activity of acetylsalicylic acid in conc. 30.3 ± 0.2 and 12.0 ± 0.3 mg/mL, respectively). Higher antiradical potential and COX-2 inhibitory properties of PHT-MLT could be explained by the presence of additional naturally occurring constituents in alfalfa, chlorella, and rice, which were clearly visible on the HPLC-ESI-QTOF-MS fingerprint. The antiradical properties of PHT-MLT determined in the DPPH test (IC₅₀ of 21.6 ± 1 mg of powder/mL) were found to originate from the presence of other metabolites in the 50% EtOH extract while SNT-MLT was found to be inactive under the applied testing conditions. However, the antioxidant studies on HaCaT keratinocytes stimulated with H₂O₂ revealed a noticeable activity in all samples. The presence of PHT-MLT (12.5, 25 and 50 µg/mL) and vitamin C (12.5, 25 and 50 µg/mL) in the H₂O₂-pretreated HaCaT keratinocytes protected the cells from generating reactive oxygen species. This observation confirms that MLT-containing samples affect the intracellular production of enzymes and neutralize the free radicals. Presented results indicated that MLT-containing products in combination with Vitamin C dosage are worth to be considered as a preventive alternative in the therapy of various diseases in the etiopathogenesis, of which radical and inflammatory mechanisms play an important role.     

Discovery of SARS-CoV-2 Mpro peptide inhibitors from modelling substrate and ligand binding

The main protease (M^pro) of SARS-CoV-2 is central to viral maturation and is a promising drug target, but little is known about structural aspects of how it binds to its 11 natural cleavage sites. We used biophysical and crystallographic data and an array of biomolecular simulation techniques, including automated docking, molecular dynamics (MD) and interactive MD in virtual reality, QM/MM, and linear-scaling DFT, to investigate the molecular features underlying recognition of the natural M^pro substrates. We extensively analysed the subsite interactions of modelled 11-residue cleavage site peptides, crystallographic ligands, and docked COVID Moonshot-designed covalent inhibitors. Our modelling studies reveal remarkable consistency in the hydrogen bonding patterns of the natural M^pro substrates, particularly on the N-terminal side of the scissile bond. They highlight the critical role of interactions beyond the immediate active site in recognition and catalysis, in particular plasticity at the S2 site. Building on our initial M^pro-substrate models, we used predictive saturation variation scanning (PreSaVS) to design peptides with improved affinity. Non-denaturing mass spectrometry and other biophysical analyses confirm these new and effective ‘peptibitors’ inhibit M^pro competitively. Our combined results provide new insights and highlight opportunities for the development of M^pro inhibitors as anti-COVID-19 drugs.

The main protease (M^pro) of SARS-CoV-2 is central to viral maturation and is a promising drug target. In silico methods reveal structural aspects of how it binds to its 11 natural cleavage sites, the design of novel peptide inhibitors, and insights into drug design.     

[2 + 3]‐Cycloadditions of Phosphonodithioformate S‐Methanides with CS,NN,and CC Dipolarophiles

The reaction of the methyl (dialkoxyphosphinyl)‐dithioformates (= methyl dialkoxyphosphinecarbodithioate 1‐oxides) 10 with CH₂N₂ at − 65° in THF yielded cycloadducts which eliminated N₂ between − 40 and − 35° to give the corresponding phosphonodithioformate S‐methanides ( =methylenesulfonium (dialkoxyoxidophosphino)(methylthio)methylides) 11 (Scheme 3). These reactive 1,3‐dipoles were intercepted by aromatic thioketones to yield 1,3‐dithiolanes. Whereas the reaction with thiobenzophenone ( 12b ) led to the sterically more congested isomers 15 regioselectively, a mixture of both regioisomers was obtained with 9H‐fluorene‐9‐thione ( 12a ). Trapping of 11 with phosphono‐ and sulfonodithioformates led exclusively to the sterically less hindered 1,3‐dithiolanes 16 and 18 , respectively (Scheme 4). In addition, reactive CC dipolarophiles such as ethenetetracarbonitrile, maleic anhydride, and N‐phenylmaleimide as well as the NN dipolarophile dimethyl diazenedicarboxylate were shown to be efficient interceptors of 11 (Scheme 5).     

Application of micellar electrokinetic chromatography for detection of silver nanoparticles released from wound dressing

The recent emergence of nanotechnology has provided a new therapeutic modality in case of silver nanoparticles. Dressings containing silver form the basis for the treatment of burns and wounds, either acute or chronic ones. The aim of the study was to examine silver release from the different wound dressings: commercially available (Atrauman Ag, Aquacel Ag) and experimental (FKDP‐AgNPs) using MEKC. In order to characterize prepared keratin based wound dressing before and after its modification with AgNPs, a compositional analysis was conducted using energy dispersive X‐ray spectroscopy. Nanosilver toxicity was evaluated with the 3‐(4,5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxyphenyl)‐2‐(4 sulfophenyl)‐2H‐tetrazolium test. Silver release from wound dressings was assessed using MEKC. The best separation was observed for MEKC in 20 mM borate buffer at pH 9 with 20 mM SDS addition. In vitro studies showed silver at higher concentration than 10 ppm exerted a toxic effect on fibroblasts isolated from diabetic mice versus. NIH/3T3 and BJ cell lines (p < 0.05). We observed silver was released more gradually from experimental FKDP‐AgNPs wound dressing, in compare to commercially available wound dressings. The fast and low‐cost method utilizing MEKC can be used in clinical practice to detect silver release from the wound dressings.     

Study on Combined Optical and Electrochemical Analysis Using Indium‐tin‐oxide‐coated Optical Fiber Sensor

In this work an optical fiber sensor, where a lossy‐mode resonance (LMR) effect was obtained due to indium tin oxide (ITO) thin overlay, has been simultaneously applied as a working electrode in a 3‐electrode cyclic voltammetry electrochemical setup. Since LMR conditions highly depend on refractive index of a surrounding medium, an LMR‐based sensor was applied for optical investigations of electrolyte's properties at the ITO surface. We have found that the optical response of the sensor highly depends on the applied potential and its changes, as well as the properties of the investigated electrolyte, i. e., its composition and presence of a redox probe. Both optical and electrochemical response of the ITO‐LMR sensor to various concentrations of phosphate‐buffered saline (PBS), NaCl and Na₂SO₄, as well as scan rate were investigated and discussed. We have found that the responses in optical and electrical domains differ significantly and may deliver supplementary information about the investigated analyte.     

Covering of nanometric calcite with α-cyclodextrin

In the present experiments, the monodisperse calcium carbonate nanoparticles obtained in the reactor (three-phase reaction) with rotating discs have been covered with α-cyclodextrin. Both pure CaCO₃ nanoparticle and α-cyclodextrin-coated CaCO₃ powders were deeply analysed by the use of the scanning electron microscope, the dynamic light scattering and the thermogravimetric method. The experimental data have allowed for determination of effective diameter of the obtained particles (aggregates of ca. 30 nm single crystals) and their size distribution (almost monodisperse—ca. 390 nm) as well as for distinction between α-cyclodextrin molecules present on calcite surface or free α-cyclodextrin molecules if presented in the sample. It was found that the nanometric CaCO₃ obtained in the reactor with rotating discs can be covered with a maximum of 1.15% α-cyclodextrin monolayer. The maximal coverage of the CaCO₃ calcite particles with α-cyclodextrin can be done by 24-h shaking of 50 mg nanometric calcium carbonate with 25 mg of 36.79 mM α-cyclodextrin aqueous solution.

     

Hydroxy lactones with the gem-dimethylcyclohexane system – Synthesis and antimicrobial activity

Two new lactones comprising the gem-dimethylcyclohexane ring: 2-chloro-5,5-dimethyl-9-oxabicyclo[4.3.0]nonan-8-one and 2-bromo-5,5-dimethyl-9-oxabicyclo[4.3.0]nonan-8-one as well as the already known 2-iodo-5,5-dimethyl-9-oxabicyclo[4.3.0]nonan-8-one, were obtained from (6,6-dimethylcyclohex-2-en-1-yl)acetic acid. These lactones were used as substrates for the screening of biotransformation by whole cells of nine fungal strains (Fusarium species, Syncephalastrum racemosum and Cunninghamella japonica). Some of these microorganisms (mainly Fusarium species) transformed all three lactones during the hydrolytic dehalogenation into 2-hydroxy-5,5-dimethyl-9-oxabicyclo[4.3.0]nonan-8-one. It is worth noting that two microorganisms (Fusarium culmorum and Fusarium scirpi) converted iodolactone with very high enantioselectivity (75.1% and 91.6%, respectively). The (+) isomer of hydroxy lactone was preferred. At the last step the hydroxy lactone obtained during biotransformation was examined for its biological activity against bacteria, yeasts and fungi. It was found that this compound inhibits growth of some tested microorganisms.     

Characterisation of Hyaluronic Acid Blends Modified by Poly(N-Vinylpyrrolidone)

The viscosity behaviour and physical properties of blends containing hyaluronic acid (HA) and poly(N-vinylpyrrolidone) (PVP) were studied by the viscometric technique, steady shear tests, tensile tests and infrared spectroscopy. Viscometric and rheological measurements were carried out using blends of HA/PVP with different HA weight fractions (0, 0.2, 0.5, 0.8 and 1). The polymer films and HA/PVP blend films were prepared using the solution casting method. The study of HA blends by viscometry showed that HA/PVP was miscible with the exception of the blend with high HA content. HA and its blends showed a shear-thinning flow behaviour. The non-Newtonian indices (n) of HA/PVP blends were calculated by the Ostwald–de Waele equation, indicating a shear-thinning effect in which pseudoplasticity increased with increasing HA contents. Mechanical properties, such as tensile strength and elongation at the break, were higher for HA/PVP films with w_HA = 0.5 compared to those with higher HA contents. The elongation at the break of HA/PVP blend films displayed a pronounced increase compared to HA films. Moreover, infrared analysis confirmed the existence of interactions between HA and PVP. The blending of HA with PVP generated films with elasticity and better properties than homopolymer films.