On machine learning analysis of atomic force microscopy images for image classification, sample surface recognition.

Atomic force microscopy (AFM or SPM) imaging is one of the best matches with machine learning (ML) analysis among microscopy techniques. The digital format of AFM images allows for direct utilization in ML algorithms without the need for additional processing. Additionally, AFM enables the simultaneous imaging of distributions of over a dozen different physicochemical properties of sample surfaces, a process known as multidimensional imaging. While this wealth of information can be challenging to analyze using traditional methods, ML provides a seamless approach to this task. However, the relatively slow speed of AFM imaging poses a challenge in applying deep learning methods broadly used in image recognition. This prospective is focused on ML recognition/classification when using a relatively small number of AFM images, aka small database. We discuss ML methods other than popular deep-learning neural networks. The described approach has already been successfully used to analyze and classify the surfaces of biological cells. It can be applied to recognize medical images, specific material processing, in forensic studies, even to identify the authenticity of arts. A general template for ML analysis specific to AFM is suggested, with a specific example of the identification of cell phenotype. Special attention is given to the analysis of the statistical significance of the obtained results, an important feature that is often overlooked in papers dealing with machine learning. A simple method for finding statistical significance is also described.

Decreased renal expression of PAQR5 is associated with the absence of a nephroprotective effect of progesterone in a rat UUO model.

Fibrosis is a severe complication of chronic kidney disease (CKD). Progesterone, like other sex hormones, plays an important role in renal physiology, but its role in CKD is poorly understood. We investigated progesterone effect on renal fibrosis progression in the rat model of unilateral ureteral obstruction (UUO). Female rats were exposed to UUO, ovariectomy and progesterone administration after UUO with ovariectomy. Expression of key fibrosis markers, proinflammatory cytokines, levels of membrane-bound (PAQR5) and nuclear (PGR) progesterone receptors, and matrix metalloproteinase (MMP) activity were analyzed in the obstructed and intact rat kidney. In all groups exposed to UUO, decreased PAQR5 expression was observed in the obstructed kidney while in the contralateral kidney, it remained unaffected. We found increased mRNA levels for profibrotic COL1A1, FN1, MMP2, TIMP1, TIMP2, proinflammatory IL1α, IL1ß, and IL18, as well as elevated α-SMA and MMP9 proteins, collagen deposition, and MMP2 activity in all UUO kidneys. Progesterone had slight or no effect on the change in these markers. Thus, we demonstrate for the first time diminished sensitivity of the kidney to progesterone associated with renal fibrosis due to a severe decrease in PAQR5 expression that was accompanied by the lack of nephroprotection in a rat UUO model.

[Methods for the identification and quantification of microplastics in foods (a review)].

The adverse effects of microplastics (MP) found in food on the health have recently been recognized as a new source of human health risks. In order to evaluate and minimize them, it is necessary to evaluate the exposure using sensitive and specific methods. The aim of the research was the substantiation of methodological approaches to the identification and quantification of microplastics in food based on the analysis of literature data. Material and methods. Literature selection was carried out using the PubMed international reference database for the period from 2014 to 2023 using keywords corresponding to the context of the research theme. A total of 159 sources were selected, of which 94 original and review papers were included in the review according to the criteria of their relevance to the problem under consideration, scientific reliability and completeness. Results. At present, various approaches have been developed that make it possible to isolate MPs from complex bioorganic matrices (such as, for example, seafood), classify them by chemical composition, and quantify their content through the mass or number of particles. Among the most developed physic-chemical methods for the analysis of MPs are Fourier transform IR spectrometry and Raman microspectrometry, pyrolysis gas chromatography - mass spectrometry, thermogravimetric analysis, as well as approaches based on liquid chromatography, microfluorimetry, analytical scanning and transmission electron microscopy and others. Unsolved problems in the field of MP research in food include the high laboriousness and low performance of the identification technologies used, the lack of reference and standard samples of MP, the complexity of the equipment used, which makes it difficult to use it for routine hygienic control. The issue of the influence of MP aging degree on the results of its qualitative and quantitative determination has not been sufficiently studied. Some hopes in the field of development of rapid analysis of MTs are pinned on the use of aptamers. Conclusion. Existing analytical methods make it possible to determine the content of MPs in environmental objects, but further improvement and validation of these methods is required in relation to the assessment of the content of MPs in various types of food.

[Assessment of the influence of an enzymal preparation - a complex of glucoamylase and xylanase from Aspergillus awamori Xyl T-15 on the intestinal microbiom and immunological indicators of rats].

The requirements for the safety of food products obtained by microbial synthesis are including as obligation for to conduct toxicological studies - the study of various biochemical and immunological markers of toxic effects. The necessity of these studies is explained by a possible change in the structure of food ingredients produced by a microbial cell and, consequently, a change in their biological properties, as well as the possible presence of living forms and/or DNA of producer strains or of their toxic metabolites in these ingredients. At the same time, it is well known that the nutrient composition of foods has a significant impact on the composition and properties of microorganisms that make up the gut microbiome, which, in turn, determines the immune status. The purpose of the research was to justify the analyses of gut microbiocenosis composition for inclusion in the protocol of safety investigation of foods obtained by microbial synthesis [on the example of an enzyme preparation (EP) - a complex of glucoamylase and xylanase from a genetically modified strain of Aspergillus awamori Xyl T-15]. Material and methods. In experimental studies carried out for 80 days, Wistar rats (males and females) were used. The study of the effect of EP (a complex of glucoamylase and xylanase from a genetically modified Aspergillus awamori Xyl T-15 strain) in dozes 10, 100 and 1000 mg/kg body mass on the cecum microbiome and the immune status (content of cytokines and chemokines: IL-1a, IL-4, IL-6, IL-10, IL-17A, INF-γ, TNF-α, MCP-1, MIP-1a and Regulated on Activation Normal T-cell Expressed and Secreted - RANTES) was carried out. Results. It has been shown that EP - a complex of glucoamylase and xylanase from A. awamori Xyl T-15 at doses of 100 mg/kg or more causes mild disturbances in the composition of gut microbiocenosis. At the same time, these disorders have a significant immunomodulat ory and immunotoxic effect on the body, which manifests itself in a dose-dependent change in the profile of pro-inflammatory cytokines and chemokines in blood and spleen. The adverse effect of EP on the body is probably due to the formation of metabolites that are not formed during usual digestive processes in the gastrointestinal tract. The minimum effective dose (LOAEL) of EP was 100 mg/kg body weight In accordance with established requirements, the activity of the EP should not appear in ready-to-use food. Subject to this requirement, amount of EP entering the body cannot exceed the established LOAEL level. Therefore, a complex of glucoamylase and xylanase can be used in food industry, subject to the establishment of regulations «for technological purposes¼ for A. awamori Xyl T-15 strain. Conclusion. The data obtained on the relationship between the state of the microbiome and the immune status upon the introduction of EP indicate the need to include indicators of the state of gut microbiocenosis in the test protocol of safety.

Cell mechanics can be robustly derived from AFM indentation data using the brush model: error analysis.

The brush model was introduced to interpret AFM indentation data collected on biological cells in a more consistent way compared just to the traditional Hertz model. It takes into account the presence of non-Hertzian deformation of the pericellular brush-like layer surrounding cells (a mix of glycocalyx molecules and microvilli/microridges). The model allows finding the effective Young's modulus of the cell body in a less depth-dependent manner. In addition, it allows finding the force due to the pericellular brush layer. Compared to simple mechanical models used to interpret the indentation experiments, the brush model has additional complexity. It raises the concern about the possible unambiguity of separation of mechanical properties of the cell body and pericellular layer. Here we present the analysis of the robustness of the brush model and demonstrate a weak dependence of the obtained results on the uncertainties within the model and experimental data. We critically analyzed the use of the brush model on a variety of AFM force curves collected on rather distinct cell types: human cervical epithelial cells, rat neurons, and zebrafish melanocytes. We conclude that the brush model is robust; the errors in the definition of the effective Young's modulus due to possible uncertainties of the model and experimental data are within 4%, which is less than the error, for example, due to a typical uncertainty in the spring constant of the AFM cantilever. We also discuss the errors of parameterization of the force due to the pericellular brush layer.

Topical Issues of Strategic Planning and Audit in Modern Russia.

The article analyzes the state of strategic planning and audit in the Russian Federation. There is a low level of implementation of the country's main strategic documents, which is due to the insufficient realism of their goals. In turn, the shortcomings of strategic documents are largely a consequence of the lack of regulatory rulemaking and the closed nature of the procedure for their development. Strategic audit in Russia is still not effective enough, since the practical significance of the recommendations of the Accounts Chamber is not great-the problems it reveals cannot be eliminated at the stage of implementation of strategic documents, and it is actually excluded from participation in their development. Based on the results of the analysis, the authors formulate proposals on the areas of improving the procedures for strategic planning and audit.

Quantum interference effects in multi-channel correlated tunneling structures.

In multi-channel tunneling systems quantum interference effects modify tunneling conductance spectra due to Fano effect. We investigated the impact of Hubbard type Coulomb interaction on tunneling conductance spectra for the system formed by several interacting impurity atoms or quantum dots localised between the contact leads. It was shown that the Fano shape of tunneling conductance spectra strongly changes in the presence of on-site Coulomb interaction between localised electrons in the intermediate system. The main effect which determines the shape of the tunneling peaks could be not Fano interference but mostly nonequilibrium dependence of the occupation numbers on bias voltage.

How to Ensure Fiscal Sustainability in Russia.

The COVID-19 pandemic and global economic crisis aggravated risks to long-term fiscal stability in Russia. The article analyzes why compliance with the fiscal rule prevents us from curbing these risks, and the way in which construction of this rule should be modified to improve its efficiency. It makes a strong case for system-based fiscal consolidation to enhance fiscal stability and presents options for optimization of spending and tax increases.

[Risk assessment of glucoamylase and xylanase complex from Aspergillus awamori Xyl T-15].

The introduction of methods for food production using microbial synthesis, including those obtained with the help of genetically modified (GM) microorganisms, at the present stage, allows to increase production volumes and reduce the cost of food. At the same time, such products in accordance with TR CU 021/2011 "On food safety" are classified as a "novel food"¼ and can be placed on the market only after its risk estimation for health. The emergence of new data and research methods in the last years has made it necessary to improve the risk assessment system for this category of food. The aim of the research is to develope risk assessment approaches of food obtained by microbial synthesis on the example of the GM strain Aspergillus awamori Xyl T-15 and the enzyme preparation (EP) (a complex of glucoamylase and xylanase) produced by it. Material and methods. Outbred ICR mice (CD-1) and Wistar rats (males and females) were used in the experimental studies. Investigations of GM strain A. awamori Xyl T-15 virulence and its ability to disseminate internal organs have been carried out. Acute and subacute (during 80 days) toxicity of EP (a complex of glucoamylase and xylanase) have been studied. Results. The presented experimental data allow us to make a conclusion about the avirulence of the A. awamori Xyl T-15 strain, the lack of ability to disseminate internal organs (invasiveness). At the same time, the strain is characterized by the ability to produce mycotoxins (ochratoxin, fumonisin B2, T-2 and HT-2 toxins). The EP, a complex of glucoamylase and xylanase from A. awamori Xyl T-15, has a low oral acute toxicity for rats (LD50>5000 mg/kg). I ntragastric EP administration at doses of 10, 100 and 1000 mg/kg of body weight during 80 days had not revealed adversely affect on the rate of weight gain in animals, indicators of anxiety and cognitive function, and some studied biochemical indicators. At a dose of 100 mg/kg b.w. or more, there were changes in the relative mass of organs (lungs, kidneys, adrenal glands), small shifts in the parameters of erythropoiesis and leukocyte formula, at a dose of 1000 mg/kg b.w. - an increase in oxidative DNA destruction. T he most pronounced and dose-dependent was the effect of the EP on hepatocyte apoptosis. According to this indicator, the not observed adverse effect level (NOAEL) for EP is not more than 100 mg/kg b.w. in terms of protein. The main target organ for the toxic effect of EP is the liver. Conclusion. The data obtained demonstrate the necessity to conduct an additional analysis of the risks of possible negative effects of EP, namely, to study its impact on the gut microbiocenosis and the immune status of experimental animals, to analyze the presence of determinants of pathogenicity and antibiotic resistance, DNA of selective marker genes of A. awamori Xyl T-15 strain by PCR analysis and DNA sequencing methods.

Modeling the voltage distribution in a non-locally but globally electroneutral confined electrolyte medium: applications for nanophysiology.

The distribution of voltage in sub-micron cellular domains remains poorly understood. In neurons, the voltage results from the difference in ionic concentrations which are continuously maintained by pumps and exchangers. However, it not clear how electro-neutrality could be maintained by an excess of fast moving positive ions that should be counter balanced by slow diffusing negatively charged proteins. Using the theory of electro-diffusion, we study here the voltage distribution in a generic domain, which consists of two concentric disks (resp. ball) in two (resp. three) dimensions, where a negative charge is fixed in the inner domain. When global but not local electro-neutrality is maintained, we solve the Poisson-Nernst-Planck equation both analytically and numerically in dimension 1 (flat) and 2 (cylindrical) and found that the voltage changes considerably on a spatial scale which is much larger than the Debye screening length, which assumes electro-neutrality. The present result suggests that long-range voltage drop changes are expected in neuronal microcompartments, probably relevant to explain the activation of far away voltage-gated channels located on the surface membrane.

Relation between generalized diffusion equations and subordination schemes.

Generalized (non-Markovian) diffusion equations with different memory kernels and subordination schemes based on random time change in the Brownian diffusion process are popular mathematical tools for description of a variety of non-Fickian diffusion processes in physics, biology, and earth sciences. Some of such processes (notably, the fluid limits of continuous time random walks) allow for either kind of description, but other ones do not. In the present work we discuss the conditions under which a generalized diffusion equation does correspond to a subordination scheme, and the conditions under which a subordination scheme does possess the corresponding generalized diffusion equation. Moreover, we discuss examples of random processes for which only one, or both kinds of description are applicable.

Ultrabright fluorescent nanothermometers.

Here we report on the first ultrabright fluorescent nanothermometers, ∼50 nm-size particles, capable of measuring temperature in 3D and down to the nanoscale. The temperature is measured through the recording of the ratio of fluorescence intensities of fluorescent dyes encapsulated inside the nanochannels of the silica matrix of each nanothermometer. The brightness of each particle excited at 488 nm is equivalent to the fluorescence coming from 150 molecules of rhodamine 6G and 1700 molecules of rhodamine B dyes. The fluorescence of both dyes is excited with a single wavelength due to the Förster resonance energy transfer (FRET). We demonstrate repeatable measurements of temperature with the uncertainty down to 0.4 K and a constant sensitivity of ∼1%/K in the range of 20-50 °C, which is of particular interest for biomedical applications. Due to the high fluorescence brightness, we demonstrate the possibility of measurement of accurate 3D temperature distributions in a hydrogel. The accuracy of the measurements is confirmed by numerical simulations. We further demonstrate the use of single nanothermometers to measure temperature. As an example, 5-8 nanothermometers are sufficient to measure temperature with an error of 2 K (with the measurement time of >0.7 s).

[On the regulate tropane alkaloids in grain products].

Tropane alkaloids (TA) are metabolites of various plant species in the families Brassicaceae, Solanaceae and Erythroxylaceae. Seeds of these weeds are found in flax, soy, sorghum, millet, sunflower, buckwheat and food products obtained from them, in herbals used as a part of food supplements and herbal teas. Despite the fact that the contamination of grain seeds by various parts of weeds reduces by sorting and clean up, a certain amount of TA gets into processed foods. An analysis of the consumption of TA with all types of foods, conducted by the European food safety Agency (EFSA), showed that TA intake with ration of various population groups can exceed the established level of single safe intake (ARfD) - 0.016 µg/kg of body weight (by 11-18% for adults, and by 5-25% for children depending on the age). The aim of the research was to justify the need to introduce regulations for the safe content of TA in grain products. Material and methods. The study process used hygiene, analytical methods, expert assessments on the basis of generalization and analysis of contemporary scientific researches published in databases Scopus, Web of Science, PubMed, RISC, Russian and international regulatory and legislative documents. Results. The established risks associated with TA contamination of grain and grain-based foods, as well as food supplements based on herbs and herbal teas, make it necessary to monitor food products for it's presence. Conclusion. Due to the greater study of the risks associated with the presence of atropine and scopolamine in foods, scientific justification of safe levels of these TA in foods based on cereals, including baby foods for children under 3 years old containi ng millet, sorghum, buckwheat or products based on these cereals is required.

Difference in biophysical properties of cancer-initiating cells in melanoma mutated zebrafish.

Despite sharing oncogenetic mutations, only a small number of cells within a given tissue will undergo malignant transformation. Biochemical and physical factors responsible for this cancer-initiation process are not well understood. Here we study biophysical differences of pre-melanoma and melanoma cells in a BRAFV600E/P53 zebrafish model. The AFM indentation technique was used to study the cancer-initiating cells while the surrounding melanocytes were the control. We observed a statistically significant decrease in the modulus of elasticity (the effective Young's modulus) of cancer-initiating cells compared to the surrounding melanocytes. No significant differences in the pericellular coat surrounding cells were observed. These results contribute to a better understanding of the factors responsible for the initiation of cancer.

Non-steady-state photo-EMF interferometer for detection of mechanical oscillations in transparent scattering objects.

The operation of an adaptive non-steady-state photo-electromagnetic field (EMF) sensor is studied in an interferometric arrangement including a diffuse scattering object-fiber optic plate. The mechanical oscillations of this plate induce the strains and stresses of the medium, which modulates the phase of the propagating light wave across the plate. The resonant frequencies of the mechanical system and the distribution of the phase modulation amplitude across the plate's surface are measured. The minimal detectable stress amplitude is estimated.

Intensity of Waves Inside a Strongly Disordered Medium.

Anderson localization does not lead to an exponential decay of intensity of an incident wave with the depth inside a strongly disordered three-dimensional medium. Instead, the average intensity is roughly constant in the first half of a disordered slab, sharply drops in a narrow region in the middle of the sample, and then remains low in the second half of the sample. A universal, scale-free spatial distribution of average intensity is found at mobility edges where the intensity exhibits strong sample-to-sample fluctuations. Our numerical simulations allow us to discriminate between two competing local diffusion theories of Anderson localization and to pinpoint a deficiency of the self-consistent theory.

Mean squared displacement in a generalized Lévy walk model.

Lévy walks represent a class of stochastic models (space-time-coupled continuous-time random walks) with applications ranging from the laser cooling to the description of animal motion. The initial model was intended for the description of turbulent dispersion as given by the Richardson law. The existence of this Richardson regime in the original model was recently challenged [T. Albers and G. Radons, Phys. Rev. Lett. 120, 104501 (2018)PRLTAO0031-900710.1103/PhysRevLett.120.104501]: The mean squared displacement (MSD) in this model diverges, i.e., does not exist, in the regime, where it presumably should reproduce the Richardson law. In the Supplemental Material to that work the authors present (but do not investigate in detail) a generalized model interpolating between the original one and the Drude-like models known to show no divergences. In the present work we give a detailed investigation of the ensemble MSD in this generalized model, show that the behavior of the MSD in this model is the same (up to prefactors) as in the original one in the domains where the MSD in the original model does exist, and investigate the conditions under which the MSD in the generalized model does exist or diverges. Both ordinary and aged situations are considered.

Noninvasive diagnostic imaging using machine-learning analysis of nanoresolution images of cell surfaces: Detection of bladder cancer.

We report an approach in diagnostic imaging based on nanoscale-resolution scanning of surfaces of cells collected from body fluids using a recent modality of atomic force microscopy (AFM), subresonance tapping, and machine-leaning analysis. The surface parameters, which are typically used in engineering to describe surfaces, are used to classify cells. The method is applied to the detection of bladder cancer, which is one of the most common human malignancies and the most expensive cancer to treat. The frequent visual examinations of bladder (cytoscopy) required for follow-up are not only uncomfortable for the patient but a serious cost for the health care system. Our method addresses an unmet need in noninvasive and accurate detection of bladder cancer, which may eliminate unnecessary and expensive cystoscopies. The method, which evaluates cells collected from urine, shows 94% diagnostic accuracy when examining five cells per patient's urine sample. It is a statistically significant improvement (P < 0.05) in diagnostic accuracy compared with the currently used clinical standard, cystoscopy, as verified on 43 control and 25 bladder cancer patients.

Random Search with Resetting: A Unified Renewal Approach.

We provide a unified renewal approach to the problem of random search for several targets under resetting. This framework does not rely on specific properties of the search process and resetting procedure, allows for simpler derivation of known results, and leads to new ones. Concentrating on minimizing the mean hitting time, we show that resetting at a constant pace is the best possible option if resetting helps at all, and derive the equation for the optimal resetting pace. No resetting may be a better strategy if without resetting the probability of not finding a target decays with time to zero exponentially or faster. We also calculate splitting probabilities between the targets, and define the limits in which these can be manipulated by changing the resetting procedure. We moreover show that the number of moments of the hitting time distribution under resetting is not less than the sum of the numbers of moments of the resetting time distribution and the hitting time distribution without resetting.

Synchronous behaviour in network model based on human cortico-cortical connections.

OBJECTIVE: We consider a network topology according to the cortico-cortical connection network of the human brain, where each cortical area is composed of a random network of adaptive exponential integrate-and-fire neurons. APPROACH: Depending on the parameters, this neuron model can exhibit spike or burst patterns. As a diagnostic tool to identify spike and burst patterns we utilise the coefficient of variation of the neuronal inter-spike interval. MAIN RESULTS: In our neuronal network, we verify the existence of spike and burst synchronisation in different cortical areas. SIGNIFICANCE: Our simulations show that the network arrangement, i.e. its rich-club organisation, plays an important role in the transition of the areas from desynchronous to synchronous behaviours.