N. I. Lobachevsky State University of Nizhny Novgorod

OBJECTIVE: Ageing is accompanied by deterioration of multiple bodily functions and inflammation, which collectively contribute to frailty. We and others have shown that frailty co-varies with alterations in the gut microbiota in a manner accelerated by consumption of a restricted diversity diet. The Mediterranean diet (MedDiet) is associated with health. In the NU-AGE project, we investigated if a 1-year MedDiet intervention could alter the gut microbiota and reduce frailty. DESIGN: We profiled the gut microbiota in 612 non-frail or pre-frail subjects across five European countries (UK, France, Netherlands, Italy and Poland) before and after the administration of a 12-month long MedDiet intervention tailored to elderly subjects (NU-AGE diet). RESULTS: Adherence to the diet was associated with specific microbiome alterations. Taxa enriched by adherence to the diet were positively associated with several markers of lower frailty and improved cognitive function, and negatively associated with inflammatory markers including C-reactive protein and interleukin-17. Analysis of the inferred microbial metabolite profiles indicated that the diet-modulated microbiome change was associated with an increase in short/branch chained fatty acid production and lower production of secondary bile acids, p-cresols, ethanol and carbon dioxide. Microbiome ecosystem network analysis showed that the bacterial taxa that responded positively to the MedDiet intervention occupy keystone interaction positions, whereas frailty-associated taxa are peripheral in the networks. CONCLUSION: Collectively, our findings support the feasibility of improving the habitual diet to modulate the gut microbiota which in turn has the potential to promote healthier ageing.

The past decade has witnessed major breakthroughs in cancer immunotherapy. This development has been largely motivated by cancer cell evasion of immunological control and consequent tumor resistance to conventional therapies. Immunogenic cell death (ICD) is considered one of the most promising ways to achieve total tumor cell elimination. It activates the T-cell adaptive immune response and results in the formation of long-term immunological memory. ICD can be triggered by many anticancer treatment modalities, including photodynamic therapy (PDT). In this review, we first discuss the role of PDT based on several classes of photosensitizers, including porphyrins and non-porphyrins, and critically evaluate their potential role in ICD induction. We emphasize the emerging trend of ICD induction by PDT in combination with nanotechnology, which represents third-generation photosensitizers and involves targeted induction of ICD by PDT. However, PDT also has some limitations, including the reduced efficiency of ICD induction in the hypoxic tumor microenvironment. Therefore, we critically evaluate strategies for overcoming this limitation, which is essential for increasing PDT efficiency. In the final part, we suggest several areas for future research for personalized cancer immunotherapy, including strategies based on oxygen-boosted PDT and nanoparticles. In conclusion, the insights from the last several years increasingly support the idea that PDT is a powerful strategy for inducing ICD in experimental cancer therapy. However, most studies have focused on mouse models, but it is necessary to validate this strategy in clinical settings, which will be a challenging research area in the future.

Background Immunotherapy represents the future of clinical cancer treatment. The type of cancer cell death determines the antitumor immune response and thereby contributes to the efficacy of anticancer therapy and long-term survival of patients. Induction of immunogenic apoptosis or necroptosis in cancer cells does activate antitumor immunity, but resistance to these cell death modalities is common. Therefore, it is of great importance to find other ways to kill tumor cells. Recently, ferroptosis has been identified as a novel, iron-dependent form of regulated cell death but whether ferroptotic cancer cells are immunogenic is unknown. Methods Ferroptotic cell death in murine fibrosarcoma MCA205 or glioma GL261 cells was induced by RAS-selective lethal 3 and ferroptosis was analyzed by flow cytometry, atomic force and confocal microscopy. ATP and high-mobility group box 1 (HMGB1) release were detected by luminescence and ELISA assays, respectively. Immunogenicity in vitro was analyzed by coculturing of ferroptotic cancer cells with bone-marrow derived dendritic cells (BMDCs) and rate of phagocytosis and activation/maturation of BMDCs (CD11c + CD86 + , CD11c + CD40 + , CD11c + MHCII + , IL-6, RNAseq analysis). The tumor prophylactic vaccination model in immune-competent and immune compromised (Rag-2 −/− ) mice was used to analyze ferroptosis immunogenicity. Results Ferroptosis can be induced in cancer cells by inhibition of glutathione peroxidase 4, as evidenced by confocal and atomic force microscopy and inhibitors’ analysis. We demonstrate for the first time that ferroptosis is immunogenic in vitro and in vivo. Early, but not late, ferroptotic cells promote the phenotypic maturation of BMDCs and elicit a vaccination-like effect in immune-competent mice but not in Rag-2 −/− mice, suggesting that the mechanism of immunogenicity is very tightly regulated by the adaptive immune system and is time dependent. Also, ATP and HMGB1, the best-characterized damage-associated molecular patterns involved in immunogenic cell death, have proven to be passively released along the timeline of ferroptosis and act as immunogenic signal associated with the immunogenicity of early ferroptotic cancer cells. Conclusions These results pave the way for the development of new therapeutic strategies for cancers based on induction of ferroptosis, and thus broadens the current concept of immunogenic cell death and opens the door for the development of new strategies in cancer immunotherapy.

Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity.

The aging process is characterized by the chronic inflammatory status called "inflammaging", which shares major molecular and cellular features with the metabolism-induced inflammation called "metaflammation." Metaflammation is mainly driven by overnutrition and nutrient excess, but other contributing factors are metabolic modifications related to the specific body composition (BC) changes occurring with age. The aging process is indeed characterized by an increase in body total fat mass and a concomitant decrease in lean mass and bone density, that are independent from general and physiological fluctuations in weight and body mass index (BMI). Body adiposity is also re-distributed with age, resulting in a general increase in trunk fat (mainly abdominal fat) and a reduction in appendicular fat (mainly subcutaneous fat). Moreover, the accumulation of fat infiltration in organs such as liver and muscles also increases in elderly, while subcutaneous fat mass tends to decrease. These specific variations in BC are considered risk factors for the major age-related diseases, such as cardiovascular diseases, type 2 diabetes, sarcopenia and osteoporosis, and can predispose to disabilities. Thus, the maintenance of a balance rate of fat, muscle and bone is crucial to preserve metabolic homeostasis and a health status, positively contributing to a successful aging. For this reason, a detailed assessment of BC in elderly is critical and could be an additional preventive personalized strategy for age-related diseases. Despite BMI and other clinical measures, such as waist circumference measurement, waist-hip ratio, underwater weighing and bioelectrical impedance, are widely used as a surrogate measure for body adiposity, they barely reflect the distribution of body fat. Because of the great advantages offered by imaging tools in research and clinics, the attention of clinicians is now moving to powerful imaging techniques such as computed tomography, magnetic resonance imaging, dual-energy X-ray absorptiometry and ultrasound to obtain a more accurate estimation of BC. The aim of this review is to present the state of the art of the imaging techniques that are currently available to measure BC and that can be applied to the study of BC changes in the elderly, outlining advantages and disadvantages of each technique.

Abstract Conductive hydrogels as flexible electronic devices, not only have unique attractions but also meet the basic need of mechanical flexibility and intelligent sensing. How to endow anisotropy and a wide application temperature range for traditional homogeneous conductive hydrogels and flexible sensors is still a challenge. Herein, a directional freezing method is used to prepare anisotropic MXene conductive hydrogels that are inspired by ordered structures of muscles. Due to the anisotropy of MXene conductive hydrogels, the mechanical properties and electrical conductivity are enhanced in specific directions. The hydrogels have a wide temperature resistance range of −36 to 25 °C through solvent substitution. Thus, the muscle‐inspired MXene conductive hydrogels with anisotropy and low‐temperature resistance can be used as wearable flexible sensors. The sensing signals are further displayed on the mobile phone as images through wireless technology, and images will change with the collected signals to achieve motion detection. Multiple flexible sensors are also assembled into a 3D sensor array for detecting the magnitude and spatial distribution of forces or strains. The MXene conductive hydrogels with ordered orientation and anisotropy are promising for flexible sensors, which have broad application prospects in human–machine interface compatibility and medical monitoring.

Abstract. With progressing global warming, there is an increased risk that one or several tipping elements in the climate system might cross a critical threshold, resulting in severe consequences for the global climate, ecosystems and human societies. While the underlying processes are fairly well-understood, it is unclear how their interactions might impact the overall stability of the Earth's climate system. As of yet, this cannot be fully analysed with state-of-the-art Earth system models due to computational constraints as well as some missing and uncertain process representations of certain tipping elements. Here, we explicitly study the effects of known physical interactions among the Greenland and West Antarctic ice sheets, the Atlantic Meridional Overturning Circulation (AMOC) and the Amazon rainforest using a conceptual network approach. We analyse the risk of domino effects being triggered by each of the individual tipping elements under global warming in equilibrium experiments. In these experiments, we propagate the uncertainties in critical temperature thresholds, interaction strengths and interaction structure via large ensembles of simulations in a Monte Carlo approach. Overall, we find that the interactions tend to destabilise the network of tipping elements. Furthermore, our analysis reveals the qualitative role of each of the four tipping elements within the network, showing that the polar ice sheets on Greenland and West Antarctica are oftentimes the initiators of tipping cascades, while the AMOC acts as a mediator transmitting cascades. This indicates that the ice sheets, which are already at risk of transgressing their temperature thresholds within the Paris range of 1.5 to 2 ∘C, are of particular importance for the stability of the climate system as a whole.

This paper reviews the basic physical notions underlying microwave sintering and the theoretical and numerical models of the microwave sintering process. The propagation and absorption of electromagnetic waves in materials, and the distribution of electromagnetic field in cavity resonators that serve as applicators for microwave processing are discussed and the electromagnetic modeling of such applicators is reviewed. The microwave absorption properties of ceramic and metal powder materials and the methods of their description are addressed. Self‐consistent electromagnetic and thermal models that are capable of predicting the temperature distribution in the microwave‐heated materials and dynamic effects such as thermal runaway instabilities are reviewed. The multiphysics simulations that combine electromagnetic, thermal, and sintering models and result in predicting densification, shrinkage, and grain structure evolution are discussed in detail. The significance of microwave nonthermal effects in sintering is demonstrated based on the experimental results, and the models of such effects are reviewed.

Single-cell transcriptomic assays have enabled the de novo reconstruction of lineage differentiation trajectories, along with the characterization of cellular heterogeneity and state transitions. Several methods have been developed for reconstructing developmental trajectories from single-cell transcriptomic data, but efforts on analyzing single-cell epigenomic data and on trajectory visualization remain limited. Here we present STREAM, an interactive pipeline capable of disentangling and visualizing complex branching trajectories from both single-cell transcriptomic and epigenomic data. We have tested STREAM on several synthetic and real datasets generated with different single-cell technologies. We further demonstrate its utility for understanding myoblast differentiation and disentangling known heterogeneity in hematopoiesis for different organisms. STREAM is an open-source software package.

Deep learning methods for image classification and object detection are overviewed. In particular we consider such deep models as autoencoders, restricted Boltzmann machines and convolutional neural networks. Existing software packages for deep learning problems are compared.

Aging is accompanied by physiological changes affecting body composition and functionality, including accumulation of fat mass at the expense of muscle mass, with effects upon morbidity and quality of life. The gut microbiome has recently emerged as a key environmental modifier of human health that can modulate healthy aging and possibly longevity. However, its associations with adiposity in old age are still poorly understood. Here we profiled the gut microbiota in a well-characterized cohort of 201 Italian elderly subjects from the NU-AGE study, by 16S rRNA amplicon sequencing. We then tested for association with body composition from dual-energy X-ray absorptiometry (DXA), with a focus on visceral and subcutaneous adipose tissue. Dietary patterns, serum metabolome and other health-related parameters were also assessed. This study identified distinct compositional structures of the elderly gut microbiota associated with DXA parameters, diet, metabolic profiles and cardio-metabolic risk factors.

<h3>Background</h3> Anti-cancer therapy is more successful when it can also induce an immunogenic form of cancer cell death (ICD). Therefore, when developing new treatment strategies, it is extremely important to choose methods that induce ICD and thereby activate anti-tumor immune response leading to the most effective destruction of tumor cells. The aim of this work was to analyze whether the clinically widely used photosensitizers, photosens (PS) and photodithazine (PD), can induce ICD when used in photodynamic therapy (PDT). <h3>Methods</h3> Cell death in murine glioma GL261 or fibrosarcoma MCA205 cells was induced by PS- or PD-PDT and cell death was analyzed by MTT or flow cytometry. Intracellular distribution of PS and PD was studied by using the laser scanning microscope. Calreticulin exposure and HMGB1 and ATP release were detected by flow cytometry, ELISA and luminescence assay, respectively. Immunogenicity in vitro was analyzed by co-culturing of dying cancer cells with bone-marrow derived dendritic cells (BMDCs) and rate of phagocytosis and maturation (CD11c⁺CD86⁺, CD11c⁺CD40⁺) of BMDCs and production of IL-6 in the supernatant were measured. In vivo immunogenicity was analyzed in mouse tumor prophylactic vaccination model. <h3>Results</h3> We determined the optimal concentrations of the photosensitizers and found that at a light dose of 20 J/cm² (λex 615–635 nm) both PS and PD efficiently induced cell death in glioma GL261 and fibrosarcoma MCA205 cells. We demonstrate that PS localized predominantly in the lysosomes and that the cell death induced by PS-PDT was inhibited by zVAD-fmk (apoptosis inhibitor) and by ferrostatin-1 and DFO (ferroptosis inhibitors), but not by the necroptosis inhibitor necrostatin-1 s. By contrast, PD accumulated in the endoplasmic reticulum and Golgi apparatus, and the cell death induced by PD-PDT was inhibited only by z-VAD-fmk. Dying cancer cells induced by PS-PDT or PD-PDT emit calreticulin, HMGB1 and ATP and they were efficiently engulfed by BMDCs, which then matured, became activated and produced IL-6. Using dying cancer cells induced by PS-PDT or PD-PDT, we demonstrate the efficient vaccination potential of ICD in vivo. <h3>Conclusions</h3> Altogether, these results identify PS and PD as novel ICD inducers that could be effectively combined with PDT in cancer therapy.

The evolution of density inhomogeneities and the velocity field in an expanding continuous medium is studied. The consideration is based on the model equation of non-linear diffusion (Burgers' equation), that, together with the equation of continuity incorporating mass density, gives an approximate description of density inhomogeneity growth at the advanced non-linear stage of gravitational instability. The model describes the formation of pancakes, filaments and compact clumps of mass as well as the disruption of the cellular and filamentary structure and the process of merging of the clumps that follows later. At this stage, the statistics of non-linear density peaks, as well as the velocity field, are determined by statistical properties of the fluctuations of the gravitational potential at linear stage. The model is in a sense an extrapolation of Zel'dovich's non-linear solution for gravitational instability of an expanding universe. It does not attempt to describe the internal structure of density enhancements but rather follows the general evolution of inhomogeneities. The model provides an analytic expression for the velocity field and makes it possible to calculate statistical characteristics of an ensemble of density clumps including their masses, velocities and spatial distribution.

Photodynamic therapy (PDT) was discovered more than 100 years ago. Since then, many protocols and agents for PDT have been proposed for the treatment of several types of cancer. Traditionally, cell death induced by PDT was categorized into three types: apoptosis, cell death associated with autophagy, and necrosis. However, with the discovery of several other regulated cell death modalities in recent years, it has become clear that this is a rather simple understanding of the mechanisms of action of PDT. New observations revealed that cancer cells exposed to PDT can pass through various non-conventional cell death pathways, such as paraptosis, parthanatos, mitotic catastrophe, pyroptosis, necroptosis, and ferroptosis. Nowadays, immunogenic cell death (ICD) has become one of the most promising ways to eradicate tumor cells by activation of the T-cell adaptive immune response and induction of long-term immunological memory. ICD can be triggered by many anti-cancer treatment methods, including PDT. In this review, we critically discuss recent findings on the non-conventional cell death mechanisms triggered by PDT. Next, we emphasize the role and contribution of ICD in these PDT-induced non-conventional cell death modalities. Finally, we discuss the obstacles and propose several areas of research that will help to overcome these challenges and lead to the development of highly effective anti-cancer therapy based on PDT.

Biological age (BA) has been proposed to evaluate the aging status instead of chronological age (CA). Our study shows evidence that there might be multiple "clocks" within the whole-body system: systemic aging drivers/clocks overlaid with organ/tissue-specific counterparts. We utilize multi-omics data, including clinical tests, immune repertoire, targeted metabolomic molecules, gut microbiomes, physical fitness examinations, and facial skin examinations, to estimate the BA of different organs (e.g., liver, kidney) and systems (immune and metabolic system). The aging rates of organs/systems are diverse. People's aging patterns are different. We also demonstrate several applications of organs/systems BA in two independent datasets. Mortality predictions are compared among organs' BA in the dataset of the United States National Health and Nutrition Examination Survey. Polygenic risk score of BAs constructed in the Chinese Longitudinal Healthy Longevity Survey cohort can predict the possibility of becoming centenarian.

COVID-19 is highly variable in its clinical presentation, ranging from asymptomatic infection to severe organ damage and death. We characterized the time-dependent progression of the disease in 139 COVID-19 inpatients by measuring 86 accredited diagnostic parameters, such as blood cell counts and enzyme activities, as well as untargeted plasma proteomes at 687 sampling points. We report an initial spike in a systemic inflammatory response, which is gradually alleviated and followed by a protein signature indicative of tissue repair, metabolic reconstitution, and immunomodulation. We identify prognostic marker signatures for devising risk-adapted treatment strategies and use machine learning to classify therapeutic needs. We show that the machine learning models based on the proteome are transferable to an independent cohort. Our study presents a map linking routinely used clinical diagnostic parameters to plasma proteomes and their dynamics in an infectious disease.

Crystalline ceramics are intensively investigated as effective materials in various nuclear energy applications, such as inert matrix and accident tolerant fuels and nuclear waste immobilization. This paper presents an analysis of the current status of work in this field of material sciences. We have considered inorganic materials characterized by different structures, including simple oxides with fluorite structure, complex oxides (pyrochlore, murataite, zirconolite, perovskite, hollandite, garnet, crichtonite, freudenbergite, and P-pollucite), simple silicates (zircon/thorite/coffinite, titanite (sphen), britholite), framework silicates (zeolite, pollucite, nepheline /leucite, sodalite, cancrinite, micas structures), phosphates (monazite, xenotime, apatite, kosnarite (NZP), langbeinite, thorium phosphate diphosphate, struvite, meta-ankoleite), and aluminates with a magnetoplumbite structure. These materials can contain in their composition various cations in different combinations and ratios: Li-Cs, Tl, Ag, Be-Ba, Pb, Mn, Co, Ni, Cu, Cd, B, Al, Fe, Ga, Sc, Cr, V, Sb, Nb, Ta, La, Ce, rare-earth elements (REEs), Si, Ti, Zr, Hf, Sn, Bi, Nb, Th, U, Np, Pu, Am and Cm. They can be prepared in the form of powders, including nano-powders, as well as in form of monolith (bulk) ceramics. To produce ceramics, cold pressing and sintering (frittage), hot pressing, hot isostatic pressing and spark plasma sintering (SPS) can be used. The SPS method is now considered as one of most promising in applications with actual radioactive substances, enabling a densification of up to 98-99.9% to be achieved in a few minutes. Characteristics of the structures obtained (e.g., syngony, unit cell parameters, drawings) are described based upon an analysis of 462 publications.

Transcriptional regulation is essential for the correct functioning of cells during development and in postnatal life. The basic Helix-loop-Helix (bHLH) superfamily of transcription factors is well conserved throughout evolution and plays critical roles in tissue development and tissue maintenance. A subgroup of this family, called neural lineage bHLH factors, is critical in the development and function of the central nervous system. In this review, we will focus on the function of one subgroup of neural lineage bHLH factors, the Neurod family. The Neurod family has four members: Neurod1, Neurod2, Neurod4, and Neurod6. Available evidence shows that these four factors are key during the development of the cerebral cortex but also in other regions of the central nervous system, such as the cerebellum, the brainstem, and the spinal cord. We will also discuss recent reports that link the dysfunction of these transcription factors to neurological disorders in humans.

Global optimization problems where evaluation of the objective function is an expensive operation arise frequently in engineering, decision making, optimal control, etc. There exist two huge but almost completely disjoint communities (they have different journals, different conferences, different test functions, etc.) solving these problems: a broad community of practitioners using stochastic nature-inspired metaheuristics and people from academia studying deterministic mathematical programming methods. In order to bridge the gap between these communities we propose a visual technique for a systematic comparison of global optimization algorithms having different nature. Results of more than 800,000 runs on 800 randomly generated tests show that both stochastic nature-inspired metaheuristics and deterministic global optimization methods are competitive and surpass one another in dependence on the available budget of function evaluations.

A radiation-reaction trapping (RRT) of electrons is revealed in the near-QED regime of laser-plasma interaction. Electrons quivering in laser pulse experience radiation reaction (RR) recoil force by radiating photons. When the laser field reaches the threshold, the RR force becomes significant enough to compensate for the expelling laser ponderomotive force. Then electrons are trapped inside the laser pulse instead of being scattered off transversely and form a dense plasma bunch. The mechanism is demonstrated both by full three-dimensional particle-in-cell simulations using the QED photonic approach and numerical test-particle modeling based on the classical Landau-Lifshitz formula of RR force. Furthermore, the proposed analysis shows that the threshold of laser field amplitude for RRT is approximately the cubic root of laser wavelength over classical electron radius. Because of the pinching effect of the trapped electron bunch, the required laser intensity for RRT can be further reduced.