Development and application of EpitopeScan, a Python3 toolset for mutation tracking in SARS-CoV-2 immunogenic epitopes.

Introduction: Outbreaks of coronaviruses and especially the recent COVID-19 pandemic emphasize the importance of immunological research in this area to mitigate the effect of future incidents. Bioinformatics approaches are capable of providing multisided insights from virus sequencing data, although currently available software options are not entirely suitable for a specific task of mutation surveillance within immunogenic epitopes of SARS-CoV-2. Method: Here, we describe the development of a mutation tracker, EpitopeScan, a Python3 package with command line and graphical user interface tools facilitating the investigation of the mutation dynamics in SARS-CoV-2 epitopes via analysis of multiple-sequence alignments of genomes over time. We provide an application case by examining three Spike protein-derived immunodominant CD4+ T-cell epitopes restricted by HLA-DRB1*04:01, an allele strongly associated with susceptibility to rheumatoid arthritis (RA). Mutations in these peptides are relevant for immune monitoring of CD4+ T-cell responses against SARS-CoV-2 spike protein in patients with RA. The analysis focused on 2.3 million SARS-CoV-2 genomes sampled in England. Results: We detail cases of epitope conservation over time, partial loss of conservation, and complete divergence from the wild type following the emergence of the N969K Omicron-specific mutation in November 2021. The wild type and the mutated peptide represent potential candidates to monitor variant-specific CD4+ T-cell responses. EpitopeScan is available via GitHub repository https://github.com/Aleksandr-biochem/EpitopeScan.

NeuroClick: software for mimicking click reaction to generate drug-like molecules permeating the blood-brain barrier.

Background: Traditional methods for chemical library generation in virtual screening often impose limitations on the accessible chemical space or produce synthetically irrelevant structures. Incorporating common chemical reactions into generative algorithms could offer significant benefits. Materials & methods: In this study, we developed NeuroClick, a graphical user interface software designed to perform in silico azide-alkyne cycloaddition, a widely utilized synthetic approach in modern medicinal chemistry. Results & conclusion: NeuroClick facilitates the generation and filtering of large combinatorial libraries at a remarkable rate of 10,000 molecules per minute. Moreover, the generated products can be filtered to identify subsets of pharmaceutically relevant compounds based on Lipinski's rule of five and blood-brain barrier permeability prediction. We demonstrate the utility of NeuroClick by generating and filtering several thousand molecules for dopamine D3 receptor ligand screening.

Using novel click chemistry algorithm to design D3R inhibitors as blood-brain barrier permeants.

Dopamine receptor D3 (D3R) has gained attention as a promising therapeutic target for neurological disorders. In this study, an innovative in silico click reaction strategy was employed to identify potential D3R binders. The ligand template, 1-phenyl-4-[4-(1H-1,2,3-triazol-5-yl)butyl]piperazine, with substitution at the 1,2,3-triazole ring, served as the starting point. Generated compounds underwent filtration based on their brain-to-blood concentration ratio (logBB), leading to the identification of 1-{4-[1-(decahydronaphthalen-1-yl)-1H-1,2,3-triazol-5-yl]butyl}-4-phenylpiperazine as the most promising candidate, displaying superior D3R affinity and blood-brain barrier (BBB) permeability compared to the reference ligand, eticlopride. Molecular dynamics simulations further supported these findings. This study presents a novel hit for designing D3R ligands and establishes a workflow utilizing in silico click chemistry to screen compounds with BBB permeability. The proposed click reaction-based algorithm holds significant potential as a valuable tool in the development of effective antipsychotic compounds.

5-(Sulfamoyl)thien-2-yl 1,3-oxazole inhibitors of carbonic anhydrase II with hydrophilic periphery.

Hydrophilic derivatives of an earlier described series of carbonic anhydrase inhibitors have been designed, prepared and profiled against a panel of carbonic anhydrase isoforms, including the glaucoma-related hCA II. For all hydrophilic derivatives, computational prediction of intraocular permeability routes showed the predominance of conjunctival rather than corneal absorption. The potentially reactive primary or secondary amine periphery of these compounds makes them suitable candidates for bioconjugation to polymeric drug carriers. As was shown previously, the most active hCA II inhibitor is efficacious in alleviating intraocular pressure in normotensive rabbits with efficacy matching that of dorzolamide.

Tunable Properties of Nature-Inspired N,N'-Alkylated Riboflavin Semiconductors.

A series of novel soluble nature-inspired flavin derivatives substituted with short butyl and bulky ethyl-adamantyl alkyl groups was prepared via simple and straightforward synthetic approach with moderate to good yields. The comprehensive characterization of the materials, to assess their application potential, has demonstrated that the modification of the conjugated flavin core enables delicate tuning of the absorption and emission properties, optical bandgap, frontier molecular orbital energies, melting points, and thermal stability. Moreover, the thin films prepared thereof exhibit smooth and homogeneous morphology with generally high stability over time.

Synthesis conditions influencing formation of MAPbBr3 perovskite nanoparticles prepared by the ligand-assisted precipitation method.

This work reports on an optimized procedure to synthesize methylammonium bromide perovskite nanoparticles. The ligand-assisted precipitation synthetic pathway for preparing nanoparticles is a cost-effective and promising method due to its ease of scalability, affordable equipment requirements and convenient operational temperatures. Nevertheless, there are several parameters that influence the resulting optical properties of the final nanomaterials. Here, the influence of the choice of solvent system, capping agents, temperature during precipitation and ratios of precursor chemicals is described, among other factors. Moreover, the colloidal stability and stability of the precursor solution is studied. All of the above-mentioned parameters were observed to strongly affect the resulting optical properties of the colloidal solutions. Various solvents, dispersion media, and selection of capping agents affected the formation of the perovskite structure, and thus qualitative and quantitative optimization of the synthetic procedure conditions resulted in nanoparticles of different dimensions and optical properties. The emission maxima of the nanoparticles were in the 508-519 nm range due to quantum confinement, as confirmed by transmission electron microscopy. This detailed study allows the selection of the best optimal conditions when using the ligand-assisted precipitation method as a powerful tool to fine-tune nanostructured perovskite features targeted for specific applications.

Microwave-Assisted Preparation of Organo-Lead Halide Perovskite Single Crystals.

The efficiency of organo-lead halide perovskite-based optoelectronic devices is dramatically lower for amorphous materials compared to highly crystalline ones. Therefore, it is challenging to optimize and scale up the production of large-sized single crystals of perovskite materials. Here, we describe a novel and original approach to preparing lead halide perovskite single crystals by applying microwave radiation during the crystallization. The microwave radiation primarily causes precise heating control in the whole volume and avoids temperature fluctuations. Moreover, this facile microwave-assisted method of preparation is highly reproducible and fully automated, it and can be applied for various different perovskite structures. In addition, this cost-effective method is expected to be easily scalable because of its versatility and low energy consumption. The crystallization process has low heat losses; therefore, only a low microwave reactor power of 8-15 W during the temperature changes and of less than 1 W during the temperature holding is needed.

Cyclic Peptide Stabilized Lead Halide Perovskite Nanoparticles.

Combining the unique properties of peptides as versatile tools for nano- and biotechnology with lead halide perovskite nanoparticles can bring exceptional opportunities for the development of optoelectronics, photonics, and bioelectronics. As a first step towards this challenge sub 10 nm methylammonium lead bromide perovskite colloidal nanoparticles have been synthetizes using commercial cyclic peptide Cyclo(RGDFK), containing 5 amino acids, as a surface stabilizer. Perovskite nanoparticles passivated with Cyclo(RGDFK) possess charge transfer from the perovskite core to the peptide shell, resulting in lower photoluminescence quantum yields, which however opens a path for the application where charge transfer is favorable.

Highly hydrophilic 1,3-oxazol-5-yl benzenesulfonamide inhibitors of carbonic anhydrase II for reduction of glaucoma-related intraocular pressure.

Four inhibitors of human carbonic anhydrase II (hCA II) were designed based on the previously reported subnanomolar 1,3-oxazole-based sulfonamide inhibitors of the enzyme to incorporate primary and secondary amine functionality in the carboxamide side chain. The new hydrophilic compounds were found to inhibit the target isoform in sub-nanomolar to low nanomolar range with a good degree of selectivity to several other hCA isoforms. The hydrophilic character of these compounds is advantageous for intraocular residence time but not for corneal permeability which generally requires that a drug be sufficiently lipophilic. Two of the four compounds investigated, however, were found to exert comparable efficacy as 1% eye drops in PBS to that of the clinically used 2% dorzolamide (Trusopt®) eye drops. This indicated that the absorption of the compounds may occur via alternative route across conjunctiva and sclera.

From random to rational: A discovery approach to selective subnanomolar inhibitors of human carbonic anhydrase IV based on the Castagnoli-Cushman multicomponent reaction.

By exploiting the power of multicomponent chemistry, a relatively small, diverse set of primary sulfonamides was synthesized and screened against a panel of human carbonic anhydrases to reveal a low-nanomolar, albeit non-selective hCA IV lead inhibitor. Investigation of the docking poses of this compound identified a hydrophilic pocket unique to hCA IV and conveniently positioned near the carboxylate functionality of the initial lead. Various residues capable of forming hydrogen bonds as well as salt bridges were placed in this pocket via a carboxamides linkage, which led to drastic improvement of potency and selectivity towards hCA IV. This improvement of the desired inhibitory profile was rationalized by the new contacts as had been envisioned. These new tool compounds were shown to possess selective, dose-dependent cytotoxicity against human glioma T98G cell line. The latter showed a substantially increased hCA IV mRNA expression under hypoxic conditions.

Density of bulk trap states of hybrid lead halide perovskite single crystals: temperature modulated space-charge-limited-currents.

Temperature-modulated space-charge-limited-current spectroscopy (TMSCLC) is applied to quantitatively evaluate the density of trap states in the band-gap with high energy resolution of semiconducting hybrid lead halide perovskite single crystals. Interestingly multicomponent deep trap states were observed in the pure perovskite crystals, which assumingly caused by the formation of nanodomains due to the presence of the mobile species in the perovskites.

Glycolated Thiophene-Tetrafluorophenylene Copolymers for Bioelectronic Applications: Synthesis by Direct Heteroarylation Polymerisation.

A series of copolymers containing a glycolated 1,4-dithienyl-2,3,5,6-tetrafluorophenylene unit copolymerized with thiophene, bithiophene, thienothiophene and 1,2,4,5-tetrafluorobenzene comonomer units were designed and synthesised by direct heteroarylation polymerisation. The optical, electrochemical, electrochromic and solid-state structural properties of the copolymers were investigated. The copolymers exhibit stable redox properties in organic solvents and promising redox properties in thin film configuration with an aqueous electrolyte. Finally, the potential of the copolymers as active materials in organic electrochemical transistors (OECTs) was assessed, and promising performance was shown as an accumulation-mode OECT material with a peak transconductance of 0.17 mS and a good on/off ratio of 105 for the thiophene copolymer.

Novel Riboflavin-Inspired Conjugated Bio-Organic Semiconductors.

Flavins are known to be extremely versatile, thus enabling routes to innumerable modifications in order to obtain desired properties. Thus, in the present paper, the group of bio-inspired conjugated materials based on the alloxazine core is synthetized using two efficient novel synthetic approaches providing relatively high reaction yields. The comprehensive characterization of the materials, in order to evaluate the properties and application potential, has shown that the modification of the initial alloxazine core with aromatic substituents allows fine tuning of the optical bandgap, position of electronic orbitals, absorption and emission properties. Interestingly, the compounds possess multichromophoric behavior, which is assumed to be the results of an intramolecular proton transfer.

Coordination Chemistry Dictates the Structural Defects in Lead Halide Perovskites.

We show the influence of species present in precursor solution during formation of lead halide perovskite materials on the structural defects of the films. The coordination of lead by competing solvent molecules and iodide ions dictate the type of complexes present in the films. Depending on the processing conditions all PbIS5 (+) , PbI2 S4, PbI3 S3 (-) , PbI4 S2 (2-) , PbI5 S2 (3-) , PbI6 (4-) and 1D (Pb2 I4 )n chains are observed by absorption measurements. Different parameters are studied such as polarity of the solvent, concentration of iodide ions, concentration of solvent molecules and temperature. It is concluded that strongly coordinating solvents will preferentially form species with a low number of iodide ions and less coordinative solvents generate high concentration of PbI6 (-) . We furthermore propose that all these plumbate ions may act as structural defects determining electronic properties of the photovoltaic films.

Lentinoid and Polyporoid Fungi, Two Generic Conglomerates Containing Important Medicinal Mushrooms in Molecular Perspective.

Polyporoid and lentinoid fungi contain the important producers of substances having immunomodulatory, antitumoral, antiviral, and antihyperlipidemic effects. The discovery of several phylogenetic lines within the lentinoid-polyporoid continuum will help with target metabolomic analysis of species still not studied in pharmacological respects. The purpose of the present work was to increase a resolution in the lentinoid-polyporoid phylogenetic zone by means of selection of both the main representatives of Lentinus-related genera and poorly known/intermediate taxa such as Lentinus suavissimus, Neofavolus spp., and the resupinate part of Polyporus (genera Perenniporia and Pachykytospora) in the context of the basic structure of the Polyporales tree. The molecular phylogeny of highlighting all the polyporoid and lentinoid nodes was reconstructed using nLSU ITS rDNA and TEF datasets. The data obtained from ITS, TEF, and LSU coincide in support of core Polyporaceae of 10 clades corresponded to the generic level and 7 of these (Cerioporus, Cladomeris, Favolus, Lentinus, Neofavolus, Picipes, and Polyporus s.str.) contain generic units characterized by polyporoid or lentinoid morphotypes. The other 2 clades containing lentinoid taxa are outside the core Polyporaceae, namely Panus (Meruliaceae, Polyporales) and Neolentinus (Gloeophyllaceae, Gloeophyllales). A new genus, Picipes, is described and 25 new combinations are proposed.

Study on mutual interactions and electronic structures of hyaluronan with Lysine, 6-Aminocaproic acid and Arginine.

Interactions between polyelectrolytes and oppositely charged surfactants have been in a great interest for several decades, yet the conventional surfactants may cause a problem in medical applications. Interactivity between polysaccharide hyaluronan (HA) and amino acids Lysine, 6-Aminocaproic acid (6-AcA), and Arginine as an alternative system is reported. The interactions were investigated by means of rheology and electric conductance and the electronic structures were explored by the density functional theory (DFT). Lysine exhibits the strongest interaction of all, which was manifested, e.g. by nearly 6-time drop of the initial viscosity comparing with only 1.3-time lower value in the case of 6-AcA. Arginine interaction with HA was surprisingly weaker in terms of viscosity than that of Lysine due to a lower and delocalized charge density on its guanidine group. According to the DFT calculations, the binding of Lysine to HA was found to be more flexible, while Arginine creates more rigid structure with HA.

Luminescent Diamond Nanoparticles: Physical, Chemical and Biological Aspects of the Phenomenon.

Biosensors based on nanodiamonds are able to penetrate through the cell membrane in a targeted manner and probe changes in real-time in the inner cellular space. In this work we performed exclusive theoretical and experimental study of nanodiamond particles adjusted for application in optically-traceable intracellular nanodiamond sensors. Theoretical and experimental study of specific optical properties of high-pressure high-temperature nanodiamonds containing NV- and NV0 centres were performed. The results are supported by theoretical modeling. The final result of this study was detection of luminescence ND in living cells and in vivo application od luminiscence NDs in chicken embryo, showing the detectability of luminescence ND using a standard confocal microscope. On the level of in cells selectivity numerous clusters of ND particles were present within the cytoplasm and at the same time no particles were absent in the nucleus-ND particles can be used as imaging or delivery system for specific cell parts targeting. From our study we can say that biosensors based on nanodiamonds (NDs) are able to penetrate through the cell membrane in a targeted manner and probe changes in the inner cellular space.

Role of vertical segregation in semitransparent organic photovoltaics.

In this work, the efficiency of semitransparent organic photovoltaic (OPV) devices for low intensity applications is investigated as a function of the processing conditions. It is observed that a thermal treatment of the organic layer induces fullerene migration toward the active layer/air interface. This physical process gives rise to different vertical segregation profiles of donor and acceptor molecules. Once the back contact is deposited, the amount of fullerene covering the surface will determine the contact selectivity and leakage current of the device. Control of this leakage current may not be essential for devices fabricated for high illumination condition applications. However, devices to be used under low illumination conditions may be highly influenced by the presence of this parasitic dark current which flows in the opposite direction to photogenerated current. At the proximity of the contacts, the vertical segregation profile is inferred from optical and electrical measurements. In particular, external quantum efficiency (EQE) measurements carried out from a relatively opaque back contact provide local information on the materials spatially close to the light source. Alternatively, capacitance-voltage measurements enable calculation of the percentage of fullerene molecules covering the cathode contact. Overall, a versatile method that can be used in regular and inverted configuration is presented that explains the different behavior observed for devices to be used under low illumination conditions.

High-efficiency deflection of high-energy protons through axial channeling in a bent crystal.

Beam deflection due to axial channeling in a silicon crystal bent along the 111 axis was observed with 400 GeV/c protons at the CERN Super Proton Synchrotron. The condition for doughnut scattering of protons by the atomic strings of the crystal was attained. Such a condition allowed one to observe a beam deflection of 50 murad with about 30% efficiency. The contribution of hyperchanneled states of protons to the observed beam deflection was less than 2% according to simulation results.

Apparatus to study crystal channeling and volume reflection phenomena at the SPS H8 beamline.

A high performance apparatus has been designed and built by the H8-RD22 collaboration for the study of channeling and volume reflection phenomena in the interaction of 400 GeV/c protons with bent silicon crystals, during the 2006 data taking in the external beamline H8 of the CERN SPS. High-quality silicon short crystals were bent by either anticlastic or quasimosaic effects. Alignment with the highly parallel (8 murad divergence) proton beam was guaranteed through a submicroradian goniometric system equipped with both rotational and translational stages. Particle tracking was possible by a series of silicon microstrip detectors with high-resolution and a parallel plate gas chamber, triggered by various scintillating detectors located along the beamline. Experimental observation of volume reflection with 400 GeV/c protons proved true with a deflection angle of (10.4+/-0.5) murad with respect to the unperturbed beam, with a silicon crystal whose (111) planes were parallel to the beam.