Selenium catalysis enables negative feedback organic oscillators.

The construction of materials regulated by chemical reaction networks requires regulatory motifs that can be stacked together into systems with desired properties. Multiple autocatalytic reactions producing thiols are known. However, negative feedback loop motifs are unavailable for thiol chemistry. Here, we develop a negative feedback loop based on the selenocarbonates. In this system, thiols induce the release of aromatic selenols that catalyze the oxidation of thiols by organic peroxides. This negative feedback loop has two important features. First, catalytic oxidation of thiols follows Michaelis-Menten-like kinetics, thus increasing nonlinearity for the negative feedback. Second, the strength of the negative feedback can be tuned by varying substituents in selenocarbonates. When combined with the autocatalytic production of thiols in a flow reactor, this negative feedback loop induces sustained oscillations. The availability of this negative feedback motif enables the future construction of oscillatory, homeostatic, adaptive, and other regulatory circuits in life-inspired systems and materials.

Expanding Predictive Capacities in Toxicology: Insights from Hackathon-Enhanced Data and Model Aggregation.

In the realm of predictive toxicology for small molecules, the applicability domain of QSAR models is often limited by the coverage of the chemical space in the training set. Consequently, classical models fail to provide reliable predictions for wide classes of molecules. However, the emergence of innovative data collection methods such as intensive hackathons have promise to quickly expand the available chemical space for model construction. Combined with algorithmic refinement methods, these tools can address the challenges of toxicity prediction, enhancing both the robustness and applicability of the corresponding models. This study aimed to investigate the roles of gradient boosting and strategic data aggregation in enhancing the predictivity ability of models for the toxicity of small organic molecules. We focused on evaluating the impact of incorporating fragment features and expanding the chemical space, facilitated by a comprehensive dataset procured in an open hackathon. We used gradient boosting techniques, accounting for critical features such as the structural fragments or functional groups often associated with manifestations of toxicity.

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.

Ultrasensitive Detection of PSA Using Antibodies in Crowding Polyelectrolyte Multilayers on a Silicon Nanowire Field-Effect Transistor.

Immunosensors based on field-effect transistors with nanowire channels (NWFETs) provide fast and real-time detection of a variety of biomarkers without the need for additional labels. The key feature of the developed immunosensor is the coating of silicon NWs with multilayers of polyelectrolytes (polyethylenimine (PEI) and polystyrene sulfonate (PSS)). By causing a macromolecular crowding effect, it ensures the "soft fixation" of the antibodies into the 3-D matrix of the oppositely charged layers. We investigated the interaction of prostate-specific antigen (PSA), a biomarker of prostate cancer, and antibodies adsorbed in the PEI and PSS matrix. In order to visualize the formation of immune complexes between polyelectrolyte layers using SEM and AFM techniques, we employed a second clone of antibodies labeled with gold nanoparticles. PSA was able to penetrate the matrix and concentrate close to the surface layer, which is crucial for its detection on the nanowires. Additionally, this provides the optimal orientation of the antibodies' active centers for interacting with the antigen and improves their mobility. NWFETs were fabricated from SOI material using high-resolution e-beam lithography, thin film vacuum deposition, and reactive-ion etching processes. The immunosensor was characterized by a high sensitivity to pH (71 mV/pH) and an ultra-low limit of detection (LOD) of 0.04 fg/mL for PSA. The response of the immunosensor takes less than a minute, and the measurement is carried out in real time. This approach seems promising for further investigation of its applicability for early screening of prostate cancer and POC systems.

Analyzing the Effects of Single Nucleotide Polymorphisms on hnRNPA2/B1 Protein Stability and Function: Insights for Anticancer Therapeutic Design.

Heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1) is a pivotal player in m6A recognition, RNA metabolism, and antiviral responses. In the context of cancer, overexpression of hnRNPA2/B1, abnormal RNA levels, and m6A depositions are evident. This study focuses on two significant nonsynonymous single nucleotide polymorphisms (nsSNPs) within hnRNPA2/B1, namely, F66L and E92K. Our structural analyses reveal decreased stability in these mutants, with E92K being predicted to undergo destabilizing post-translational methylation. Furthermore, our extensive analysis of 44,239 tumor samples from the COSMIC database uncovers that amino acid position 92 exhibits the second-highest mutation frequency within hnRNPA2/B1, particularly associated with breast and lung cancers. This experimental data aligns with our theoretical studies, highlighting the substantial impact of the nsSNP at position 92 on hnRNPA2/B1's stability and functionality. Given the critical role of pre-mRNA splicing, transcription, and translation regulation in cellular function, it is important to assess the impact of these nsSNPs on the stability and function of the hnRNPA2/B1 protein to design more efficient anticancer therapeutics.

Voronoi Entropy as a Ligand Molecular Descriptor of Protein-Ligand Interactions.

We investigate the correlation between the Voronoi entropy (VE) of ligand molecules and their affinity to receptors to test the hypothesis that less ordered ligands have higher mobility of molecular groups and therefore a higher probability of attaching to receptors. VE of 1144 ligands is calculated using SMILES-based 2D graphs representing the molecular structure. The affinity of the ligands with the SARS-CoV-2 main protease is obtained from the BindingDB Database as half-maximal inhibitory concentration (IC50) data. The VE distribution is close to the Gaussian, 0.4 ≤ Sv ≤ 1.66, and a strong correlation with IC50 is found, IC50 = -275 Sv + 613 nM, indicating the correlation between ligand complexity and affinity. On the contrary, the Shannon entropy (SE) descriptor failed to provide enough evidence to reject the null hypothesis (p-value > 0.05), indicating that the spatial arrangement of atoms is crucial for molecular mobility and binding.

Electrochemical Sensor to Detect Antibiotics in Milk Based on Machine Learning Algorithms.

The present study is dedicated to the problem of electrochemical analysis of multicomponent mixtures, such as milk. A combination of cyclic voltammetry facilities and machine learning techniques made it possible to create a pattern recognition system for the detection of antibiotic residues in skimmed milk. A multielectrode sensor including copper, nickel, and carbon fiber was fabricated for the collection of electrochemical data. Processes occurring at the electrode surface were discussed and simulated with the help of molecular docking and density functional theory modeling. It was assumed that the antibiotic fingerprint reveals a potential drift of electrodes, owing to complexation with metal ions present in milk. The gradient boosting algorithm showed the best efficiency in training the machine learning model. High accuracy was achieved for the recognition of antibiotics in milk. The elaborated method may be incorporated into existing milking systems at dairy farms for monitoring the residue concentrations of antibiotics.

Deposition of Nanostructured Tungsten Oxide Layers by a New Method: Periodic Modulation of the Deposition Angle.

Periodic modulation of the deposition angle (PMDA) is a new method to deposit nanostructured and continuous layers with controllable periodic density fluctuation. The method is used for the magnetron sputtering of a WO3 layer for an electrochromic device (ECD). An experimental study indicates that the electrochromic coloration-bleaching rate nearly doubles and the electrochromic efficiency grows by about 25% in comparison with the traditional method. The ECD efficiency rises with the increasing degree of nanostructure ordering, surface roughness, and homogeneity of the WO3 layer. The method is promising for coating deposition techniques needed to produce versatile devices with specific requirements for ion transport in surface layers, coatings, and interfaces, such as fuel cells, batteries, and supercapacitors.

Diffusion-Limited Processes in Hydrogels with Chosen Applications from Drug Delivery to Electronic Components.

Diffusion is one of the key nature processes which plays an important role in respiration, digestion, and nutrient transport in cells. In this regard, the present article aims to review various diffusion approaches used to fabricate different functional materials based on hydrogels, unique examples of materials that control diffusion. They have found applications in fields such as drug encapsulation and delivery, nutrient delivery in agriculture, developing materials for regenerative medicine, and creating stimuli-responsive materials in soft robotics and microrobotics. In addition, mechanisms of release and drug diffusion kinetics as key tools for material design are discussed.

Universal Method Based on Layer-by-Layer Assembly for Aptamer-Based Sensors for Small-Molecule Detection.

Development of a fast and accurate pesticide analysis system is a challenging task, as a large amount of commonly used pesticide has negative effects on humans' health. Detection of pesticide residues is crucial for food safety management and environmental protection. Aptamers─short single-stranded oligonucleotides (RNA or DNA) selected by aptamer selection method SELEX─can selectively bind to their target pesticide molecules with high affinity. Thus, in the present study, we developed an electrochemical biosensor based on aptamers to detect the commonly used pesticide, glyphosate. Carbon fibers were used as the platform to assemble polyelectrolyte layers with the incorporated aptamers selectively binding with glyphosate molecules for electrochemical detection. The best limit of detection of 0.3 µM was achieved at open-circuit potential measurements, which is comparable to the current need in detection of glyphosate. The developed method can be implemented into existing systems for the determination of pesticides on farms to control residual concentrations of glyphosate in soil and water.

Calix[4]arene-pyrazole conjugates as potential cancer therapeutics.

Tumor selectivity is yet a challenge in chemotherapy-based cancer treatment. A series of calixarenes derivatized at the lower rim with 3-phenyl-1H-pyrazole units with variable upper-rim substituent and conformations of macrocyclic core, alkyl chain length between heterocycle and core, as well as phenolic monomer (5-(4-tert-butylphenyloxy)methoxy-3-phenyl-1H-pyrazole) have been synthesized and characterized in a range of therapeutically relevant cellular models (M-HeLa, MCF7, A-549, PC3, Chang liver, and Wi38) from different target organs/systems. Specific cytotoxicity for M-HeLa cells has been observed in tert-butylcalix[4]arene pyrazoles in 1,3-alternate (compound 7b) and partial cone (compound 7c) conformations with low mutagenicity and haemotoxicity and in vivo toxicity in mice. Compounds 7b,c have induced mitochondrial pathway of apoptosis of M-HeLa cells through caspase-9 activation preceded by the cell cycle arrest at G0/G1 phase. A concomitant overexpression of DNA damage markers in pyrazole-treated M-HeLa cells suggests that calixarene pyrazoles target DNA, which was supported by the presence of interactions between calixarenes and ctDNA at the air-water interface.

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.

Memristive Effect in Ti3 C2 Tx (MXene) Polyelectrolyte Multilayers.

The emerging novel class of two-dimensional materials - MХenes - have attracted significant research attention. However, there are only few reports on using the most prominent member of the MXene family, Ti3 C2 Tx , as an active material for memristive devices within a polyelectrolyte matrix and its deposition on inert electrodes like ITO and Pt. In this study, we systematically investigate Ti3 C2 Tx MXenes synthesized with two classical delamination agents, such as lithium chloride and tetramethylammonium hydroxide, to identify the most suitable candidate for memristive device applications. The characteristics of memristors based on the hybrid structures consisting of MXene-polyelectrolyte multilayers, specifically polyethyleneimine (PEI) and poly(sodium 4-styrenesulfonate) (PSS) are explored. The PEI(MXene)/PSS memristor exhibits a voltage threshold (VSET/RESET ) range of 1.5-2.0 V, enabling the transition from a high-resistive state (HRS) to a low-resistive state (LRS), along with a significant current switching ratio of approximately two orders of magnitude. The observed VSET/RESET difference of approximately 4 V is further supported by density functional theory (DFT) calculated redox potential. These findings underscore the potential of polyelectrolyte-based memristors, such as the in PEI-Ti3 C2 Tx -PSS system, in facilitating the development of highly functional, self-assembled memristive devices with diverse applications.

Folding-unfolding asymmetry and a RetroFold computational algorithm.

We treat protein folding as molecular self-assembly, while unfolding is viewed as disassembly. Fracture is typically a much faster process than self-assembly. Self-assembly is often an exponentially decaying process, since energy relaxes due to dissipation, while fracture is a constant-rate process as the driving force is opposed by damping. Protein folding takes two orders of magnitude longer than unfolding. We suggest a mathematical transformation of variables, which makes it possible to view self-assembly as time-reversed disassembly, thus folding can be studied as reversed unfolding. We investigate the molecular dynamics modelling of folding and unfolding of the short Trp-cage protein. Folding time constitutes about 800 ns, while unfolding (denaturation) takes only about 5.0 ns and, therefore, fewer computational resources are needed for its simulation. This RetroFold approach can be used for the design of a novel computation algorithm, which, while approximate, is less time-consuming than traditional folding algorithms.

Melamine Barbiturate as a Light-Induced Nanostructured Supramolecular Material for a Bioinspired Oxygen and Organic Radical Trap and Stabilization.

Use of coantioxidant systems is a prospective way to increase the effectiveness of antioxidant species in tissue repair and regeneration. In this paper, we introduce a novel scheme of a reactive oxygen species (ROS) trap and neutralization during self-assembly of supramolecular melamine barbiturate material. The performed reaction chain mimics the biological process of ROS generation in key stages and enables one to obtain stable hydroperoxyl and organic radicals in a melamine barbiturate structure. Melamine barbiturate also neutralizes hydroxyl radicals, and the effectiveness of the radical trap is controlled with ROS scavenger incorporation. The number of radicals dramatically increases during light-inducing and depends on pH. The proposed scheme of the ROS trap and neutralization opens a way to the use of supramolecular assemblies as a component of coantioxidant systems and a source of organic radicals.

Functionalization of chitosan with poly aromatic hydroxyl molecules for improving its antibacterial and antioxidant properties: Practical and theoretical studies.

In this study, the chitosan backbone was functionalized with 2,2',4,4'-tetrahydroxybenzophenone by Schiff base, bonding the molecules into the repeating amine groups. The use of 1H NMR, FT-IR, and UV-Vis analyses provided compelling evidence of the structure of the newly developed derivatives. The deacetylation degree was calculated to be 75.35 %, and the degree of substitution was 5.53 % according to elemental analysis. The thermal analysis of samples using TGA demonstrated that CS-THB derivatives are more stable than chitosan itself. SEM was used to investigate the change in surface morphology. The improvement of the biological properties of chitosan was investigated in terms of its antibacterial activity against pathogenic antibiotic-resistant bacteria. The antioxidant properties showed an improvement in activity compared to chitosan by two times against ABTS radicals and four times against DPPH radicals. Furthermore, the cytotoxicity and anti-inflammatory properties were investigated using normal skin cells (HBF4) and WBCs. Quantum chemistry calculations revealed that combining polyphenol with chitosan makes it more effective as an antioxidant than either chitosan or polyphenol alone. Our findings suggest that the new chitosan Schiff base derivative could be utilized for tissue regeneration applications.

Ergodicity Breaking and Self-Destruction of Cancer Cells by Induced Genome Chaos.

During the progression of some cancer cells, the degree of genome instability may increase, leading to genome chaos in populations of malignant cells. While normally chaos is associated with ergodicity, i.e., the state when the time averages of relevant parameters are equal to their phase space averages, the situation with cancer propagation is more complex. Chromothripsis, a catastrophic massive genomic rearrangement, is observed in many types of cancer, leading to increased mutation rates. We present an entropic model of genome chaos and ergodicity and experimental evidence that increasing the degree of chaos beyond the non-ergodic threshold may lead to the self-destruction of some tumor cells. We study time and population averages of chromothripsis frequency in cloned rhabdomyosarcomas from rat stem cells. Clones with frequency above 10% result in cell apoptosis, possibly due to mutations in the BCL2 gene. Potentially, this can be used for suppressing cancer cells by shifting them into a non-ergodic proliferation regime.

Uricase Crowding via Polyelectrolyte Layers Coacervation for Carbon Fiber-Based Electrochemical Detection of Uric Acid.

Urate oxidase (UOx) surrounded by synthetic macromolecules, such as polyethyleneimine (PEI), poly(allylamine hydrochloride) (PAH), and poly(sodium 4-styrenesulfonate) (PSS) is a convenient model of redox-active biomacromolecules in a crowded environment and could display high enzymatic activity towards uric acid, an important marker of COVID-19 patients. In this work, the carbon fiber electrode was modified with Prussian blue (PB) redox mediator, UOx layer, and a layer-by-layer assembled polyelectrolyte film, which forms a complex coacervate consisting of a weakly charged polyelectrolyte (PEI or PAH) and a highly charged one (PSS). The film deposition process was controlled by cyclic voltammetry and scanning electron microscopy coupled with energy-dispersive X-ray analysis (at the stage of PB deposition) and through quartz crystal microbalance technique (at latter stages) revealed uniform distribution of the polyelectrolyte layers. Variation of the polyelectrolyte film composition derived the following statements. (1) There is a linear correlation between electrochemical signal and concentration of uric acid in the range of 10-4-10-6 M. (2) An increase in the number of polyelectrolyte layers provides more reproducible values for uric acid concentration in real urine samples of SARS-CoV-2 patients measured by electrochemical enzyme assay, which are comparable to those of spectrophotometric assay. (3) The PAH/UOx/PSS/(PAH/PSS)2-coated carbon fiber electrode displays the highest sensitivity towards uric acid. (4) There is a high enzyme activity of UOx immobilized into the hydrogel nanolayer (values of the Michaelis-Menten constant are up to 2 µM) and, consequently, high affinity to uric acid.

Reaction-Diffusion Pathways for a Programmable Nanoscale Texture of the Diamond-SiC Composite.

The diamond-SiC composite has a low density and the highest possible speed of sound among existing materials except for diamond. The composite is synthesized by a complex exothermic chemical reaction between diamond powder and liquid Si. This makes it an ideal material for protection against impact loading. Experiments show that a system of patterns is formed at the diamond-SiC interface. Modeling of reaction-diffusion processes of composite synthesis proves a formation of ceramic materials with a regular (periodic) interconnected microstructure in a given system. The composite material with interconnected structures at the interface has very high mechanical properties and resistance to impact since its fractioning is intercrystallite.

Piezo-Responsive Hydrogen-Bonded Frameworks Based on Vanillin-Barbiturate Conjugates.

A concept of piezo-responsive hydrogen-bonded π-π-stacked organic frameworks made from Knoevenagel-condensed vanillin-barbiturate conjugates was proposed. Replacement of the substituent at the ether oxygen atom of the vanillin moiety from methyl (compound 3a) to ethyl (compound 3b) changed the appearance of the products from rigid rods to porous structures according to optical microscopy and scanning electron microscopy (SEM), and led to a decrease in the degree of crystallinity of corresponding powders according to X-ray diffractometry (XRD). Quantum chemical calculations of possible dimer models of vanillin-barbiturate conjugates using density functional theory (DFT) revealed that π-π stacking between aryl rings of the vanillin moiety stabilized the dimer to a greater extent than hydrogen bonding between carbonyl oxygen atoms and amide hydrogen atoms. According to piezoresponse force microscopy (PFM), there was a notable decrease in the vertical piezo-coefficient upon transition from rigid rods of compound 3a to irregular-shaped aggregates of compound 3b (average values of d33 coefficient corresponded to 2.74 ± 0.54 pm/V and 0.57 ± 0.11 pm/V), which is comparable to that of lithium niobate (d33 coefficient was 7 pm/V).