Serum Beta-Defensin-2 is a biomarker for psoriasis but not subclinical atherosclerosis: Role of IL17a, PI-3 kinase and Rac1.

Background: Beta-defensins (BDs) are antimicrobial peptides secreted upon epithelial injury. Both chemotactic and antimicrobial properties of BDs function as initial steps in host defense and prime the adaptive immune system in the body. Psoriasis, a chronic immune-mediated inflammatory disease, has both visible cutaneous manifestations as well as known associations with higher incidence of cardiometabolic complications and vascular inflammation. Objectives: We aimed to investigate the circulating expression of beta-defensin-2 (BD2) in psoriasis at baseline compared to control subjects, along with changes in BD2 levels following biologic treatment at one-year. The contribution of BD2 to subclinical atherosclerosis is also assessed. In addition, we have sought to unravel signaling mechanisms linking inflammation with BD2 expression. Methods: Multimodality imaging as well inflammatory biomarker assays were performed in biologic naïve psoriasis (n=71) and non-psoriasis (n=53) subjects. A subset of psoriasis patients were followed for one-year after biological intervention (anti-Tumor Necrosis Factor-α (TNFα), n=30; anti-Interleukin17A (IL17A), n=21). Measurements of circulating BD2 were completed by Enzyme-Linked Immunosorbent Assay (ELISA). Using HaCaT transformed keratinocytes, expression of BD2 upon cytokine treatment was assessed by quantitative polymerase chain reaction (qPCR) and ELISA. Results: Herein, we confirm that human circulating BD2 levels associate with psoriasis, which attenuate upon biologic interventions (anti-TNFα, anti-IL-17A). A link between circulating BD2 and sub-clinical atherosclerosis markers was not observed. Furthermore, we demonstrate that IL-17A-driven BD2 expression occurs in a Phosphatidylinositol 3-kinase (PI3-kinase) and Rac1 GTPase-dependent manner. Conclusions: Our findings expand on the potential role of BD2 as a tractable biomarker in psoriasis patients and describes the role of an IL-17A-PI3-kinase/Rac signaling axis in regulating BD2 levels in keratinocytes.

Novel biocatalysts based on enzymes in complexes with nano- and micromaterials.

In today's world, there is a wide array of materials engineered at the nano- and microscale, with numerous applications attributed to these innovations. This review aims to provide a concise overview of how nano- and micromaterials are utilized for enzyme immobilization. Enzymes act as eco-friendly biocatalysts extensively used in various industries and medicine. However, their widespread adoption faces challenges due to factors such as enzyme instability under different conditions, resulting in reduced effectiveness, high costs, and limited reusability. To address these issues, researchers have explored immobilization techniques using nano- and microscale materials as a potential solution. Such techniques offer the promise of enhancing enzyme stability against varying temperatures, solvents, pH levels, pollutants, and impurities. Consequently, enzyme immobilization remains a subject of great interest within both the scientific community and the industrial sector. As of now, the primary goal of enzyme immobilization is not solely limited to enabling reusability and stability. It has been demonstrated as a powerful tool to enhance various enzyme properties and improve biocatalyst performance and characteristics. The integration of nano- and microscale materials into biomedical devices is seamless, given the similarity in size to most biological systems. Common materials employed in developing these nanotechnology products include synthetic polymers, carbon-based nanomaterials, magnetic micro- and nanoparticles, metal and metal oxide nanoparticles, metal-organic frameworks, nano-sized mesoporous hydrogen-bonded organic frameworks, protein-based nano-delivery systems, lipid-based nano- and micromaterials, and polysaccharide-based nanoparticles.

Optimizing the generation of polarization squeezed light in nonlinear optical fibers driven by femtosecond pulses.

Bright squeezed light can be generated in optical fibers utilizing the Kerr effect for ultrashort laser pulses. However, pulse propagation in a fiber is subject to nonconservative effects that deteriorate the squeezing. Here, we analyze two-mode polarization squeezing, which is SU(2)-invariant, robust against technical perturbations, and can be generated in a polarization-maintaining fiber. We perform a rigorous numerical optimization of the process and the pulse parameters using our advanced model of quantum pulse evolution in the fiber that includes various nonconservative effects and real fiber data. Numerical results are consistent with experimental results.

Implementation of rapid microwave sintering using a 24 GHz gyrotron system.

Rapid microwave sintering of different oxide ceramics with heating rates up to 300 °C/min and zero hold time has been implemented using a 24 GHz gyrotron-based system for high-temperature processing of materials. The design of the system, principle of operation, and process control are described. Particular attention is given to the design of thermal insulation assemblies and the implementation of temperature measurement in an environment with intense electromagnetic fields. A description of an optical system for dilatometry and temperature measurement is presented. The interrelation between the automatically regulated output power of the gyrotron and the microwave power absorbed volumetrically in the sample is analyzed on the basis of energy balance considerations. The analysis is illustrated by considering examples of rapid sintering processes with ZnO-based and BaTiO3 ceramic samples making use of direct and susceptor-assisted microwave heating. It is demonstrated that an increase in the volumetrically absorbed power leads to the development of a controlled thermal instability, which results in a lower temperature of the densification onset.

Changes in the Microbiome of Milk in Cows with Mastitis.

Analysis of milk micrbiomes from healthy cows and cows with different (clinical and subclinical) forms of mastitis was performed at two farms of the Central Russia. An increase in the operational taxonomic units (OTUs) of bacteria of the phylum Proteоbacteria belonging primarily to Pseudomonadales, Burkholderiales, as well as Streptococcaceae, Staphylococcaceae, and Bacillaceae in the animals with mastitis was detected. The Planococcaceae OTU percentage decreased. The ratio of rarely presented OTUs also changed in the milk of animals with mastitis.

[Analysis of phosphatidylcholines alterations in human glioblastoma multiform tissues ex vivo]. / Analiz izmenenii sostava fosfatidilkholinov v glioblastomakh cheloveka ex vivo.

Significant metabolism alteration is accompanying the cell malignization process. Energy metabolism disturbance leads to the activation of de novo synthesis and beta-oxidation processes of lipids and fatty acids in a cancer cell, which becomes an indicator of pathological processes inside the cell. The majority of studies dealing with lipid metabolism alterations in glial tumors are performed using the cell lines in vitro or animal models. However, such conditions do not entirely represent the physiological conditions of cell growth or possible cells natural variability. This work presents the results of the data obtained by applying ambient mass spectrometry to human glioblastoma multiform tissues. By analyzing a relatively large cohort of primary and secondary glioblastoma samples, we identify the alterations in cells lipid composition, which accompanied the development of grade IV brain tumors. We demonstrate that primary glioblastomas, as well as ones developed from astrocytomas, are enriched with mono- and diunsaturated phosphatidylcholines (PC 26:1, 30:2, 32:1, 32:2, 34:1, 34:2). Simultaneously, the saturated and polyunsaturated phosphatidylcholines and phosphatidylethanolamines decrease. These alterations are obviously linked to the availability of the polyunsaturated fatty acids and activation of the de novo lipid synthesis and beta-oxidation pathways under the anaerobic conditions in the tumor core.

The software for interactive evaluation of mass spectra stability and reproducibility.

SUMMARY: Mass spectrometry (MS) methods are widely used for the analysis of biological and medical samples. Recently developed methods, such as DESI, REIMS and NESI allow fast analyses without sample preparation at the cost of higher variability of spectra. In biology and medicine, MS profiles are often used with machine learning (classification, regression, etc.) algorithms and statistical analysis, which are sensitive to outliers and intraclass variability. Here, we present spectra similarity matrix (SSM) Display software, a tool for fast visual outlier detection and variance estimation in mass spectrometric profiles. The tool speeds up the process of manual spectra inspection, improves accuracy and explainability of outlier detection, and decreases the requirements to the operator experience. It was shown that the batch effect could be revealed through SSM analysis and that the SSM calculation can also be used for tuning novel ion sources concerning the quality of obtained mass spectra. AVAILABILITY AND IMPLEMENTATION: Source code, example datasets, binaries and other information are available at https://github.com/EvgenyZhvansky/R_matrix. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

[The role of lipids in the classification of astrocytoma and glioblastoma using MS tumor profiling]. / Rol' lipidov pri klassifikatsii astrotsitomy i glioblastomy pri pomoshchi mass-spektrometricheskogo profilirovaniia opukholei.

Express MS identification of biological tissues has become a much more accessible research method due to the application of direct specimen ionization at atmospheric pressure. In contrast to traditional methods of analysis employing GC-MS methods for determining the molecular composition of the analyzed objects it eliminates the influence of mutual ion suppression. Despite significant progress in the field of direct MS of biological tissues, the question of mass spectrometric profile attribution to a certain type of tissue still remains open. The use of modern machine learning methods and protocols (e.g., "random forests") enables us to trace possible relationships between the components of the sample MS profile and the result of brain tumor tissue classification (astrocytoma or glioblastoma). It has been shown that the most pronounced differences in the mass spectrometric profiles of these tumors are due to their lipid composition. Detection of statistically significant differences in lipid profiles of astrocytoma and glioblastoma may be used to perform an express test during surgery and inform the neurosurgeon what type of malignant tissue he is working with. The ability to accurately determine the boundaries of the neoplastic growth significantly improves the quality of both surgical intervention and postoperative rehabilitation, as well as the duration and quality of life of patients.

Update of ion-optical system of neutral beam of Tokamak à Configuration Variable.

An injector of fast deuterium atoms for plasma heating was designed and installed at the Tokamak à Configuration Variable (TCV). The neutral beam can deliver 1 MW power to the plasma in 2 s pulses. An ion beam of the injector is formed by a triode multislit ion-optical system with spherical electrodes which provide ballistic focusing. Tests at TCV revealed that the total angular divergence of the neutral beam across the slits exceeded the expected value more than twice. It was finally established that this increase in divergence was caused by the asymmetry of the chamfers at the slit edges of the plasma electrode. The redesigned shape of the slits of the plasma grid together with precise machining significantly improved the beam quality. Experimental testing proved that the neutral beam profile in the direction across the grid slits became very close to the expected value.

Triple blockade of EGFR, MEK and PD-L1 has antitumor activity in colorectal cancer models with constitutive activation of MAPK signaling and PD-L1 overexpression.

BACKGROUND: Molecular mechanisms driving acquired resistance to anti-EGFR therapies in metastatic colorectal cancer (mCRC) are complex but generally involve the activation of the downstream RAS-RAF-MEK-MAPK pathway. Nevertheless, even if inhibition of EGFR and MEK could be a strategy for overcoming anti-EGFR resistance, its use is limited by the development of MEK inhibitor (MEKi) resistance. METHODS: We have generated in vitro and in vivo different CRC models in order to underline the mechanisms of MEKi resistance. RESULTS: The three different in vitro MEKi resistant models, two generated by human CRC cells quadruple wild type for KRAS, NRAS, BRAF, PI3KCA genes (SW48-MR and LIM1215-MR) and one by human CRC cells harboring KRAS mutation (HCT116-MR) showed features related to the gene signature of colorectal cancer CMS4 with up-regulation of immune pathway as confirmed by microarray and western blot analysis. In particular, the MEKi phenotype was associated with the loss of epithelial features and acquisition of mesenchymal markers and morphology. The change in morphology was accompanied by up-regulation of PD-L1 expression and activation of EGFR and its downstream pathway, independently to RAS mutation status. To extend these in vitro findings, we have obtained mouse colon cancer MC38- and CT26-MEKi resistant syngeneic models (MC38-MR and CT26-MR). Combined treatment with MEKi, EGFR inhibitor (EGFRi) and PD-L1 inhibitor (PD-L1i) resulted in a marked inhibition of tumor growth in both models. CONCLUSIONS: These results suggest a strategy to potentially improve the efficacy of MEK inhibition by co-treatment with EGFR and PD-L1 inhibitors via modulation of host immune responses.

Metrics for evaluating the stability and reproducibility of mass spectra.

In this work, we demonstrate a new approach for assessing the stability and reproducibility of mass spectra obtained via ambient ionization methods. This method is suitable for both comparing experiments during which only one mass spectrum is measured and for evaluating the internal homogeneity of mass spectra collected over a period of time. The approach uses Pearson's r coefficient and the cosine measure to compare the spectra. It is based on the visualization of dissimilarities between measurements, thus leading to the analysis of dissimilarity patterns. The cosine measure and correlations are compared to obtain better metrics for spectra homogeneity. The method filters out unreliable scans to prevent the analyzed sample from being wrongly characterized. The applicability of the method is demonstrated on a set of brain tumor samples. The developed method could be employed in neurosurgical applications, where mass spectrometry is used to monitor the intraoperative tumor border.

Unified representation of high- and low-resolution spectra to facilitate application of mass spectrometric techniques in clinical practice.

The majority of research in the biomedical sciences is carried out with the highest resolution accessible to the scientist, but, in the clinic, cost constraints necessitate the use of low-resolution devices. Here, we compare high- and low-resolution direct mass spectrometry profiling data and propose a simple pre-processing technique that makes high-resolution data suitable for the development of classification and regression techniques applicable to low-resolution data, while retaining high accuracy of analysis. This work demonstrates an approach to de-noising spectra to make the same representation for both high- and low-resolution spectra. This approach uses noise threshold detection based on the Tversky index, which compares spectra with different resolutions, and minimizes the percentage of resolution-specific peaks. The presented method provides an avenue for the development of analytical algorithms using high-resolution mass spectrometry data, while applying these algorithms in the clinic using low-resolution mass spectrometers.

[Destabilization of the DNA Duplex of Actively Replicating Promoters of T7-Like Bacteriophages].

The relation between the processes of replication and transcription has been actively studied over several decades, but detailed mechanisms for their interaction have not been established reliably. Among the initiating transcription promoters of bacteria and bacteriophages, there are both promoters having an additional function of the secondary origin of replication (OR) and promoters not participating in this process. In this paper, we describe the stability of DNA by Stress-Induced Duplex Destabilization (SIDD) profiles for a complete set of promoters and the primary OR of the bacteriophage T7 genome. It has been shown that, among the native T7 promoters, only those that have an additional function of secondary OR are characterized by high destabilization. These include the phiOL and phiOR promoters adjoining the 5' and 3' terminal repeats of bacteriophage T7, and of six other T7 group phages. In each case, these two promoters are located in the regions of DNA with high destabilization of the duplex. Additionally, the genomes of seven representatives of the T7 group without annotated phiOL and phiOR have been considered. For three of them, high peaks of SIDD profiles have been found near the ends of the genomic DNA that may be due to the presence of similar phiOL and phiOR promoters. Probably, such promoters can be found in the genomes of other bacteriophages. Thus, for the promoters of bacteriophages, we have a confirmation of the relationship of SIDD as a DNA duplex parameter and the DNA replication initiation on promoters, serving as secondary OR.

[The use of immunomodulators, antioxidants and hepatoprotectors for the correction of the liver, erythrocites and the immune system disorders in chronic ethanol intoxication]. / Ispol'zovanie immunomoduliatorov, antioksidantov i gepatoprotektorov dlia korrektsii narushenii v pecheni, éritrotsitakh i immunnoi sisteme pri khronicheskoi intoksikatsii étanolom.

The effectiveness of three various combinations of an immunomodulator with an antioxidant and a membrane protector in the correction of metabolic and immune disorders has been studied in the experiment under 60-days ethanol intoxication. The development of such biochemical syndromes of the liver damage as cytolysis, intrahepatic, intracellular cholestasis, toxic liver damage by necrotic type, insufficiency of synthetic processes and inflammatory has been revealed. Oxidative stress development and the activation of lipid peroxidation on the systemic (blood plasma) and local level (erythrocytes) have been established. Suppression of adaptive immunity formation and phagocytic capabilities of neutrophils under the increase in their oxygen-dependent activity has been determined, which indicates the presence and possible progression of the inflammatory process at the systemic level. A disorder of erythrocytes metabolic activity, a decrease in stable metabolites of nitric oxide detected in blood plasma been revealed, indicating its uncompensated consumption, causing vasoconstriction and thrombosis, which can additionally arise due to the established increase in the prothrombin index. Combined use of "Longidasa", "Mexicor", "Essentiale forte N" or "Glutoxim", "Mexidol", "Heptral" was more effective in the correction of immune-metabolic disorders in chronic alcohol intoxication than "Hepon", "Hypoxen" and "Phosphogliv".

Excimer Emission of Acridine Orange Adsorbed on Gadolinium-Yttrium Orthovanadate Nanoparticles.

Studying the complexes of inorganic nanoparticles - organic dye molecules is of great importance for their theranostics application. In this paper, we report gadolinium-yttrium orthovanadate nanoparticles (VNPs) - Acridine Orange (AO) complex formation in water solutions. To study the interactions between VNPs and AO, the methods of steady-state and time-resolved spectroscopy were used. It was shown that in aqueous solutions containing VNPs, AO aggregation takes place with a sandwich-like stacking of AO molecules in the near-surface layer of VNPs. The VNPs-AO complex formation causes significant changes in the AO fluorescence spectrum, namely, the appearance of a new broad, structureless band in the long-wavelength spectral edge, which was not observed in AO spectrum in a pure water solution. By analyzing of the absorption, fluorescence excitation spectra and fluorescence decay, the static excimer origin of the long-wavelength fluorescence band has been established.

Creation of nanosized holes in graphene planes for improvement of rate capability of lithium-ion batteries.

Holes with an average size of 2-5 nm have been created in graphene layers by heating of graphite oxide (GO) in concentrated sulfuric acid followed by annealing in an argon flow. The hot mineral acid acts simultaneously as a defunctionalizing and etching agent, removing a part of oxygen-containing groups and lattice carbon atoms from the layers. Annealing of the holey reduced GO at 800 °C-1000 °C causes a decrease of the content of residual oxygen and the interlayer spacing thus producing thin compact stacks from holey graphene layers. Electrochemical tests of the obtained materials in half-cells showed that the removal of oxygen and creation of basal holes lowers the capacity loss in the first cycle and facilitates intercalation-deintercalation of lithium ions. This was attributed to minimization of electrolyte decomposition reactions, easier desolvation of lithium ions near the hole boundaries and appearance of multiple entrances for the naked ions into graphene stacks.

High-resolution mass spectra processing for the identification of different pathological tissue types of brain tumors.

The purpose of the work is to demonstrate the possibilities of identifying the different types of pathological tissue identification directly through tissue mass spectrometry. Glioblastoma parts dissected during neurosurgical operation were investigated. Tumor fragments were investigated by the immunohistochemistry method and were identified as necrotic tissue with necrotized vessels, necrotic tissue with tumor stain, tumor with necrosis (tumor tissue as major), tumor, necrotized tumor (necrotic tissues as major), parts of tumor cells, boundary brain tissue, and brain tissue hyperplasia. The technique of classification of tumor tissues based on mass spectrometric profile data processing is suggested in this paper. Classifiers dividing the researched sample to the corresponding tissue type were created as a result of the processing. Classifiers of necrotic and tumor tissues are shown to yield a combined result when the tissue is heterogeneous and consists of both tumor cells and necrotic tissue.

Determination of the conformal-field-theory central charge by the Wang-Landau algorithm.

We present a simple method to estimate the central charge of the conformal field theory corresponding to a critical point of a two-dimensional lattice model from Monte Carlo simulations. The main idea is to use the Wang-Landau flat-histogram algorithm, which allows us to obtain the free energy of a lattice model on a torus as a function of torus radii. The central charge is calculated with good precision from a free-energy scaling at the critical point. We apply the method to the Ising, tricritical Ising (Blume-Capel), Potts, and site-diluted Ising models, and we also discuss an estimation of the conformal weights.

Semiclassical bifurcations and topological phase transitions in a one-dimensional lattice of coupled Lipkin-Meshkov-Glick models.

In this work we study a one-dimensional lattice of Lipkin-Meshkov-Glick models with alternating couplings between nearest-neighbors sites, which resembles the Su-Schrieffer-Heeger model. Typical properties of the underlying models are present in our semiclassical-topological hybrid system, allowing us to investigate an interplay between semiclassical bifurcations at mean-field level and topological phases. Our results show that bifurcations of the energy landscape lead to diverse ordered quantum phases. Furthermore, the study of the quantum fluctuations around the mean-field solution reveals the existence of nontrivial topological phases. These are characterized by the emergence of localized states at the edges of a chain with free open-boundary conditions.

[The maternal effect in infantile autism: elevated DNA damage degree in patients and their mothers]. / Materinskii éffekt pri detskom autizme: povyshennyi uroven' povrezhdenii DNK u patsientov i ikh materei.

Infantile autism is a common disorder of mental development, which is characterized by impairments in the communicative, cognitive and speech spheres and obsessional stereotyped behaviour. Although in most cases, pathogenic factors remain unclear, infantile autism has a significant hereditary component, however, its etiology is also under the influence of environmental factors, including the condition of the mother's body during pregnancy ("maternal effect"). Oxidative stress is assumed to play a key role in the pathogenesis of infantile autism. It is known that oxidative stress has a prominent genotoxic effect, which is realized through inducing single and double strand breaks of the nuclear DNA. We evaluated the degree of DNA damage in patients with infantile autism and their mothers using DNA comet assay. The comet tail moment and DNA per cent ratio in the tail were assessed for each individual. The two parameters appeared to be strongly correlated (r=0.90). Mean and median values of both parameters were considerably higher in the sample of autistic children, than in age-matching healthy controls. Interestingly, these parameters were also elevated in healthy mothers of autistic children, with no difference from the values in the group of autistic children. The control group of healthy women of reproductive age, who had no children with autism, differed by the DNA comet tail moment from the group of mothers of autistic children, but did not differ significantly from the control group of healthy children. The results suggest that there are genotoxic factors in mentally healthy mothers of autistic children, which can determine the pathological process in the foeti via environmental "maternal effect" during gestation.