Functional State Research Articles

Aging trajectories of memory CD8 + T cells differ by their antigen specificity.

Memory T cells are a highly dynamic and heterogeneous population that is maintained by cytokine-driven homeostatic proliferation interspersed with episodes of antigen-mediated expansion and contraction which affect their functional state and their durability. This heterogeneity complicates studies on the impact of aging on global human memory cells, specifically, it is unclear how aging drives memory T cell dysfunction. Here, we used chronic infection with Epstein-Barr virus (EBV) to assess the influence of age on memory states at the level of antigen-specific CD8 + T cells. We find that in young adults (<40 years), EBV-specific CD8 + T cells assume preferred differentiation states depending on their peptide specificity. By age >65-years, different T cell specificities had undergone largely distinct aging trajectories, which had in common a loss in adaptive and a gain in innate immunity signatures. No evidence was seen for cellular senescence or exhaustion. While naïve/stem-like EBV-specific T cells disappeared with age, T cell diversity of EBV-specific memory cells did not change or even increased. In summary, by controlling for antigen specificity we uncover age-associated shifts in gene expression and TCR diversity that have implications for optimizing vaccination strategies and adoptive T cell therapy.

Cryopreservation of stem cell-derived beta-like cells enriches for insulin-producing cells with improved function.

The generation of stem cell-derived beta-like cells (sBC) holds extreme promise as not only an abundant insulin-producing cell source for replacement therapy of Type 1 diabetes (T1D), but also as an invaluable model system for investigating human beta cell development, immunogenicity, and function. Several groups have developed methodology to direct differentiate human pluripotent stem cells into pancreatic cell populations that include glucose responsive sBC. Nevertheless, the process of generating sBC poses significant experimental challenges. It involves lengthy differentiation periods, experiences substantial variability in efficiency, and inconsistencies in obtaining functional sBC. Here, we described a simple and effective cryopreservation approach for sBC cultures that yields homogeneous sBC clusters that are enriched for insulin expressing cells while simultaneous depleting proliferative progenitors. Thawed sBC display enhanced glucose-stimulated insulin release compared to controls in vitro and can effectively engraft and function in vivo. Collectively, this approach alleviates current challenges with inefficient and variable sBC generation while improving their functional state. We anticipate that these findings can inform ongoing clinical application of sBC for the treatment of patients with T1D and serve as an important resource for the wider diabetes field that will allow for accelerated research discoveries.

Functional architecture of intracellular oscillations in hippocampal dendrites

Fast electrical signaling in dendrites is central to neural computations that support adaptive behaviors. Conventional techniques lack temporal and spatial resolution and the ability to track underlying membrane potential dynamics present across the complex three-dimensional dendritic arbor in vivo. Here, we perform fast two-photon imaging of dendritic and somatic membrane potential dynamics in single pyramidal cells in the CA1 region of the mouse hippocampus during awake behavior. We study the dynamics of subthreshold membrane potential and suprathreshold dendritic events throughout the dendritic arbor in vivo by combining voltage imaging with simultaneous local field potential recording, post hoc morphological reconstruction, and a spatial navigation task. We systematically quantify the modulation of local event rates by locomotion in distinct dendritic regions, report an advancing gradient of dendritic theta phase along the basal-tuft axis, and describe a predominant hyperpolarization of the dendritic arbor during sharp-wave ripples. Finally, we find that spatial tuning of dendritic representations dynamically reorganizes following place field formation. Our data reveal how the organization of electrical signaling in dendrites maps onto the anatomy of the dendritic tree across behavior, oscillatory network, and functional cell states.

PPAR-γ/NF-kB/AQP3 axis in M2 macrophage orchestrates lung adenocarcinoma progression by upregulating IL-6

Aquaporin 3 (AQP3), which is mostly expressed in pulmonary epithelial cells, was linked to lung adenocarcinoma (LUAD). However, the underlying functions and mechanisms of AQP3 in the tumor microenvironment (TME) of LUAD have not been elucidated. Single-cell RNA sequencing (scRNA-seq) was used to study the composition, lineage, and functional states of TME-infiltrating immune cells and discover AQP3-expressing subpopulations in five LUAD patients. Then the identifications of its function on TME were examined in vitro and in vivo. AQP3 was associated with TNM stages and lymph node metastasis of LUAD patients. We classified inter- and intra-tumor diversity of LUAD into twelve subpopulations using scRNA-seq analyses. The analysis showed AQP3 was mainly enriched in subpopulations of M2 macrophages. Importantly, mechanistic investigations indicated that AQP3 promoted M2 macrophage polarization by the PPAR-γ/NF-κB axis, which affected tumor growth and migration via modulating IL-6 production. Mixed subcutaneous transplanted tumor mice and Aqp3 knockout mice models were further utilized, and revealed that AQP3 played a critical role in mediating M2 macrophage polarization, modulating glucose metabolism in tumors, and regulating both upstream and downstream pathways. Overall, our study demonstrated that AQP3 could regulate the proliferation, migration, and glycometabolism of tumor cells by modulating M2 macrophages polarization through the PPAR-γ/NF-κB axis and IL-6/IL-6R signaling pathway, providing new insight into the early detection and potential therapeutic target of LUAD.

Pbp4 provides transpeptidase activity to the FtsW-PbpB peptidoglycan synthase to drive cephalosporin resistance in Enterococcus faecalis.

Enterococci exhibit intrinsic resistance to cephalosporins, mediated in part by the class B penicillin-binding protein (bPBP) Pbp4 that exhibits low reactivity toward cephalosporins and thus can continue crosslinking peptidoglycan despite exposure to cephalosporins. bPBPs partner with cognate SEDS (shape, elongation, division, and sporulation) glycosyltransferases to form the core catalytic complex of peptidoglycan synthases that synthesize peptidoglycan at discrete cellular locations, although the SEDS partner for Pbp4 is unknown. SEDS-bPBP peptidoglycan synthases of enterococci have not been studied, but some SEDS-bPBP pairs can be predicted based on sequence similarity. For example, FtsW (SEDS)-PbpB (bPBP) is predicted to form the catalytic core of the peptidoglycan synthase that functions at the division septum (the divisome). However, PbpB is readily inactivated by cephalosporins, raising the question-how could the FtsW-PbpB synthase continue functioning to enable growth in the presence of cephalosporins? In this work, we report that the FtsW-PbpB peptidoglycan synthase is required for cephalosporin resistance of Enterococcus faecalis, despite the fact that PbpB is inactivated by cephalosporins. Moreover, Pbp4 associates with the FtsW-PbpB synthase and the TPase activity of Pbp4 is required to enable growth in the presence of cephalosporins in an FtsW-PbpB-synthase-dependent manner. Overall, our results implicate a model in which Pbp4 directly interacts with the FtsW-PbpB peptidoglycan synthase to provide TPase activity during cephalosporin treatment, thereby maintaining the divisome SEDS-bPBP peptidoglycan synthase in a functional state competent to synthesize crosslinked peptidoglycan. These results suggest that two bPBPs coordinate within the FtsW-PbpB peptidoglycan synthase to drive cephalosporin resistance in E. faecalis.

Improvement of Immune Function and Redox State in Several Organs of Old and Prematurely Aging Female Mice After a Short Social Interaction With Adults.

Aging is associated with chronic oxidative stress, which contributes to the deterioration of the immune system, increasing morbidity and mortality. A positive social environment permits health maintenance and a slower rate of aging. Improvements in immune function and oxidative stress were shown in peritoneal leukocytes and organs of old mice and adult prematurely aging mice (PAM) after cohabitation with adults or exceptional non-prematurely aging mice (ENPAM), respectively, for 2 months, but adults and ENPAM experienced deterioration. This was solved by shortening the cohabitation time to 15 minutes per day for 2 months, where old mice and PAM maintained immune and redox state improvements in their peritoneal leukocytes, as well as a greater longevity, and adults and ENPAM did not show deterioration. However, it is unknown whether the positive effects of this short cohabitation are reflected in the immunity and redox state of the organs. The aim of the present study was to test whether a cohabitation of 15 minutes per day for 2 months maintains these positive effects in the organs of retired breeder female old mice and PAM and avoids the negative ones in adults and ENPAM. After cohabitation the animals were sacrificed, and the thymus and spleen were extracted to evaluate the immune function. The oxidative state was also analyzed in the spleen, liver, heart, lung, and kidney. The results show that after cohabitation, old mice and PAM improved their immunity and redox state, and adults and ENPAM showed no deterioration. This cohabitation can be suggested to improve health and slow down aging.

Asynchronous motor functional state monitoring based on the relative deviations of the power losses

Asynchronous motor functional state monitoring based on the relative deviations of the power losses

Eye Movements and Autonomic Regulation of Cognitive Activity during Reading in Adolescence. Part I. Functional “Cost” of Cognitive Activity when Reading Text from the Screen in Adolescence

Reading from the screen of an electronic device (ED) is a significant cognitive activity for adolescences, and its complexity affects visceral functions. We conducted an analysis of the heart rate variability (HRV) and eye movements (EM) in adolescents while they were reading complex text on an ED screen. The aim was to assess the functional state characteristics under these conditions and reveal the intensity (“cost”) associated with this activity The study involved 22 adolescences with an average age of 15 years (М = 15.46, SD = 0.44). Reading text from an ED screen in adolescents was associated with a high functional “cost,” characterized by a decrease in overall HRV, an increase in the tension index and heart rate. These changes indicate the functional tension of regulatory systems during cognitive activity. The study revealed varying levels of parafoveal processing involvement. For the majority of adolescents (86.4%), word-by-word reading and a low percentage of regressions (12.0%) were observed, suggesting developed average reading skill. However, a qualitative analysis of individual EM tracks indicated varying level of reading skill development among adolescents, possibly due to a limited vocabulary and a lack of understanding of syntax. Additionally, 40.9% of adolescents demonstrated poor text comprehension. Our results showed that reading remains a complex cognitive task for adolescents, despite the expectation that their reading skills should be well-developed and automated by this age. Individual analysis of HRV and EM in adolescents with varying levels of text comprehension during reading demonstrated different strategies of adaptive behavior and autonomic reactions when performing a complex cognitive task. The functional “cost” of information processing when reading text from the ED screen results from a combination of age-related and individual adaptation characteristics, language competence and the psycholinguistic complexity of the text.

Viral and Bacterial Community Dynamics in Food Waste and Digestate from Full-Scale Biogas Plants.

Anaerobic digestion (AD) is commonly used in food waste treatment. Prokaryotic microbial communities in AD of food waste have been comprehensively studied. The role of viruses, known to affect microbial dynamics and metabolism, remains largely unexplored. This study employed metagenomic analysis and recovered 967 high-quality viral bins within food waste and digestate derived from 8 full-scale biogas plants. The diversity of viral communities was higher in digestate. In silico predictions linked 20.8% of viruses to microbial host populations, highlighting possible virus predators of key functional microbes. Lineage-specific virus-host ratio varied, indicating that viral infection dynamics might differentially affect microbial responses to the varying process parameters. Evidence for virus-mediated gene transfer was identified, emphasizing the potential role of viruses in controlling the microbiome. AD altered the specific process parameters, potentially promoting a shift in viral lifestyle from lysogenic to lytic. Viruses encoding auxiliary metabolic genes (AMGs) were involved in microbial carbon and nutrient cycling, and most AMGs were transcriptionally expressed in digestate, meaning that viruses with active functional states were likely actively involved in AD. These findings provided a comprehensive profile of viral and bacterial communities and expanded knowledge of the interactions between viruses and hosts in food waste and digestate.

Integrative analysis reveals the potential prognostic roles and immunological values of unc-5 netrin receptor A (UNC5A) in glioma

BackgroundUNC5A had been reported to play crucial roles in multiple cancers. However, little was known about the associations among UNC5A and glioma. Therefore, we first combined scRNA-seq, proteomics, as well as bulk RNA-seq in order to investigate UNC5A’s functions in gliomas.MethodsOnline databases provided scRNA-seq, proteomics, as well as bulk RNA-seq data on UNC5A in gliomas. The following procedures were conducted in order: QRT-PCR, Norman chart, gene set enrichment analysis (GSEA), and univariate/multifactor Cox regression analyses. We further explored the associations among UNC5A and tumor immunity.ResultsBy comparing gliomas with normal tissues, the TCGA dataset showed a significantly reduced expression of UNC5A, which was also confirmed by GSE50161, GSE4290, and QRT-PCR findings (p < 0.05). In both the TCGA and CGGA datasets, gliomas patients with low-UNC5A expression would have poorer overall survival (OS) prognoses (p < 0.05). ScRNA-seq analysis by the CancerSEA online website presented that UNC5A had a low expression in various glioma clusters and significantly associated with six functional states. Moreover, UNC5A might be a reliable independent biomarker of OS in gliomas patients (p < 0.05). Based on the results of GSEA, UNC5A might be connected to three significant pathways in gliomas. We also successfully created a Norman chart to assess the OS prognoses of these patients. Additionally, in aspects of tumor immunity, the infiltration levels of immune cells in LGG, the immune cell pathways, tumor immune microenvironment, as well as immune checkpoints in both LGG and GBM were revealed to be significantly influenced by UNC5A (p < 0.05).ConclusionsUNC5A was found to have prognostic and immunological significance in gliomas, offering patients with gliomas new treatment options.

Internet-Based Trauma Recovery Intervention for Nurses: A Randomized Controlled Trial

Introduction: Nurses, who care for patients with various traumas, may also experience post-traumatic stress disorder due to indirect or direct exposure to traumatic situations. This study examined the effectiveness of an Internet-based trauma recovery intervention for Korean nurses. Methods: This randomized controlled trial was conducted with 112 nurses aged 23–40 years who were randomly assigned to the intervention (n = 56) or control group (n = 56) from May 7 to December 20, 2020. Nurses in the intervention group attended eight sessions, and the same intervention was administered to the control group. Repeated measures were collected at pre-test, post-test 1 (immediately after the intervention), and post-test 2 (4 weeks after the intervention). A total of 102 nurses (intervention group: n = 49; control group: n = 53) were completed because 10 nurses dropped out before the first session. Data were analyzed using the χ2 test, Fisher’s exact test, t-test, Mann-Whitney U test, and repeated measures ANOVA (intention-to-treat and per protocol). Results: There were significant changes in functional health, resilience, post-traumatic stress, depressive symptoms, state anxiety, and trait anxiety over time and in the group-by-time interactions (intention-to-treat and per protocol). There was a significant difference in social support in the group-by-time interactions, but there were no significant changes between the two groups or over time (intention-to-treat and per protocol). Conclusion: The Internet-based trauma recovery nursing intervention is effective in clinical and community settings for nurses who cannot participate in fixed-schedule programs due to shift work. This study’s findings are relevant for implementing Internet-based trauma recovery programs for nurses and the general population, including survivors and relatives of patients who suffered from COVID-19. This program will also be very useful for people in other high-stress situations. Nurse leaders should consider different populations and situations when offering effective coping strategies suitable for changing environments.

Global compositional and functional states of the human gut microbiome in health and disease.

The human gut microbiota is of increasing interest, with metagenomics a key tool for analyzing bacterial diversity and functionality in health and disease. Despite increasing efforts to expand microbial gene catalogs and an increasing number of metagenome-assembled genomes, there have been few pan-metagenomic association studies and in-depth functional analyses across different geographies and diseases. Here, we explored 6014 human gut metagenome samples across 19 countries and 23 diseases by performing compositional, functional cluster, and integrative analyses. Using interpreted machine learning classification models and statistical methods, we identified Fusobacterium nucleatum and Anaerostipes hadrus with the highest frequencies, enriched and depleted, respectively, across different disease cohorts. Distinct functional distributions were observed in the gut microbiomes of both westernized and nonwesternized populations. These compositional and functional analyses are presented in the open-access Human Gut Microbiome Atlas, allowing for the exploration of the richness, disease, and regional signatures of the gut microbiota across different cohorts.

Factors and level of physical performance of schoolchildren aged 13–14 years

There is an insufficiency of data on the characteristics of physical performance of schoolchildren in the critical period of ontogenesis associated with pubertal development.The aim of the study. To determine the factors and level of physical performance of schoolchildren aged 13–14 years, taking into account pubertal development.Methodology. The study involved healthy male adolescents aged 13–14 years (n = 165). Five stages of puberty were determined. To diagnose the level of physical performance, a complex of functional and ergometric tests and a battery of motor tests were used. The structure of performance was determined based on the factor analysis.Results and discussion. We determined the factors characterizing physical performance: aerobic capacity; absolute aerobic power; anaerobic alactic performance; anaerobic glycolytic performance; relative aerobic power. The identified factors are associated with zones of relative power. It has been established that during puberty, changes in indicators combined into different factors occur non-linearly and non-simultaneously. The results of the study show that subjects of the same age with stages II, III and IV of puberty differ in the level of key bioenergetic performance criteria. Transition to higher stages of puberty is accompanied with progressive dynamics of most indicators associated with factors of anaerobic performance, while indicators of aerobic power and capacity change in different directions, showing in some cases a tendency to temporarily decrease.Conclusion. It is advisable to use the results of the study when organizing various types of monitoring the functional state and regulation of aerobic and anaerobic physical activity in adolescents aged 13–14 years at different stages of puberty. The obtained materials can serve as a scientific basis for improving the physical education system in order to increase the functional capabilities of children’s bodies during the critical period of ontogenesis associated with pubertal development

Multi-domain interaction mediated strength-building in human α-actinin dimers unveiled by direct single-molecule quantification

α-Actinins play crucial roles in cytoskeletal mechanobiology by acting as force-bearing structural modules that orchestrate and sustain the cytoskeletal framework, serving as pivotal hubs for diverse mechanosensing proteins. The mechanical stability of α-actinin dimer, a determinant of its functional state, remains largely unexplored. Here, we directly quantify the force-dependent lifetimes of homo- and hetero-dimers of human α-actinins, revealing an ultra-high mechanical stability of the dimers associated with > 100 seconds lifetime within 40 pN forces under shear-stretching geometry. Intriguingly, we uncover that the strong dimer stability is arisen from much weaker sub-domain pair interactions, suggesting the existence of distinct dimerized functional states of the dimer, spanning a spectrum of mechanical stability, with the spectrin repeats (SRs) in folded or unfolded conformation. In essence, our study supports a potent mechanism for building strength in biomolecular dimers through weak, multiple sub-domain interactions, and illuminates multifaceted roles of α-actinin dimers in cytoskeletal mechanics and mechanotransduction.

A single-use cartridge based on an acoustic sensor for a portable device for rapid assessment of the functional state of the hemostasis system

A single-use cartridge based on an acoustic sensor for a portable device for rapid assessment of the functional state of the hemostasis system

Progress in multifactorial single-cell chromatin profiling methods.

Chromatin states play a key role in shaping overall cellular states and fates. Building a complete picture of the functional state of chromatin in cells requires the co-detection of several distinct biochemical aspects. These span DNA methylation, chromatin accessibility, chromosomal conformation, histone posttranslational modifications, and more. While this certainly presents a challenging task, over the past few years many new and creative methods have been developed that now enable co-assay of these different aspects of chromatin at single cell resolution. This field is entering an exciting phase, where a confluence of technological improvements, decreased sequencing costs, and computational innovation are presenting new opportunities to dissect the diversity of chromatin states present in tissues, and how these states may influence gene regulation. In this review, I discuss the spectrum of current experimental approaches for multifactorial chromatin profiling, highlight some of the experimental and analytical challenges, as well as some areas for further innovation.

Relationship between central hemodynamic parameters and body composition and the functional state of neuro-autonomic regulation in young men

The aim of the study is to examine the relationship between central hemodynamic parameters and body composition by considering baseline functional state of neuro-autonomic regulation according to the index of regulatory system activity (IRSA) in young men. Material and methods. A total of 44 male participants were divided into three groups based on the IRSA level. The first group included 26 men with an optimal IRSA level. The second and third groups, each of 9 men, with moderate and high IRSA levels, respectively. The functional state of cardiovascular system was assessed using a device “REOKOM” (Kharkiv). The measurement of body composition was performed by weight-scale “TANITA BC-601” (Japan). The functional state of autonomic nervous system was assessed using a device “CARDIOLAB” (Kharkiv). Results. Our results have demonstrated higher hemodynamic parameters in men with moderate and high level of IRSA. Men with elevated level of sympathetic activity had the highest indices of the pumping function of the heart, and those with the balance between parasympathetic and sympathetic branches had the lowest indices of the pumping heart function. As for the indicators of total peripheral resistance and specific peripheral resistance, another trend was seen, namely, individuals with a balanced state of autonomic nervous regulation had the highest parameters, and those with a predominance of sympathetic tone had the lowest ones. Close correlations have been found between increased levels of regulatory mechanism tension and cardiohemodynamic parameters. An indicator analysis of the body component composition has revealed a significant increase in body mass index, total and visceral fat content in the examined groups with moderate and severe regulatory system tension. In addition, correlations have been found between IRSA and constituting components of body composition. Conclusions. The group assignment of the examined individuals according to IRSA has shown that a high tension of the regulatory mechanisms increased the load on the cardiovascular system, as indicated by higher indicators of central hemodynamics. In individuals with an optimal level of regulatory system functioning, the cardiovascular system activity is optimal and less energy consuming.

Effect of impaired myocardial contractility on coronary flow reserve and inflammatory processes in chronic coronary syndrome

Aim. To study the relationship between myocardial contractility impairment in chronic coronary syndrome and the state of coronary flow reserve, the degree of systemic inflammation and endothelial dysfunction. Materials and methods. We examined 120 patients with stable angina pectoris (SAP) of functional class (FC) II–III, who were assigned into two groups: group 1 comprised 65 patients with left ventricular ejection fraction (LVEF) ≥55 %, and group 2 was composed of 55 patients with LVEF &lt;55 %. Diagnostic methods included clinical and instrumental examination data, analyses of lipid profile, inflammation biomarkers, endothelial functional state, hemogram data, leukocyte inflammation markers, and questionnaires. Results. Compared to group 1, group 2 patients showed an increase in the left atrium (p &lt; 0.001) and right ventricle (p = 0.027) sizes; significantly lower LVEF (50.16 ± 0.42 % vs 58.77 ± 0.41 %; p &lt; 0.001); thickening of the intima-media complex in the right (p = 0.003) and left (p = 0.017) common carotid arteries; significantly lower load threshold values (p = 0.008), exercise tolerance (p = 0.004) and heart rate variability indicators – SDNN (standard deviation of normal-to-normal intervals over 24 hours; p = 0.046). Group 2 patients were characterized by more active low-grade chronic inflammation, as indicated by increased levels of leukocytes (p = 0.024), neutrophils (p &lt; 0.001), and decreased lymphocyte levels (p = 0.021); significantly higher levels of leukocyte inflammation markers, in particular, the neutrophil-to-lymphocyte ratio (p &lt; 0.001), platelet-to-lymphocyte ratio (p = 0.004), systemic immune-inflammation index (p &lt; 0.001), systemic inflammation response index (p &lt; 0.001), and aggregate index of systemic inflammation (p &lt; 0.001) as compared to group 1 individuals. Patients with LVEF &lt;55 % had higher levels of fibrinogen (p &lt; 0.001), uric acid (p = 0.002), high-sensitivity C-reactive protein (p = 0.007), and endothelin-1 (p &lt; 0.001) compared to those with LVEF ≥55 %. Conclusions. Group 2 patients need a more thorough monitoring and a more intensive treatment aimed at reducing the inflammatory process.

Formation of students’ systemic skills of self-control of functional state in physical education classes

Formation of students’ systemic skills of self-control of functional state in physical education classes

FEATURES OF EXPRESS RELAXATION DURING OCULAR MOTOR SYSTEM OVERLOAD

The work is devoted to determining the peculiarities of applying muscle express relaxation technique in cases of ocular motor apparatus overload. Variants of endurance of the convergent- accommodative apparatus of the eye in the subjects were identified. A correlation between the results of relaxation exercises and the type of endurance of the ocular motor apparatus was established. Positive results of applying the proposed exercises with palming according to the method of M.S. Norbekov were observed in individuals with active and moderate types of ocular motor apparatus endurance. Unsatisfactory results of applying the proposed relaxation method in cases of ocular apparatus overload were determined in individuals with slow endurance of the convergent-accommodative apparatus.Conclusions: 1. Evaluation of the endurance of the convergent-accommodative apparatus of the eye is an informative indicator of the functional state of the visual organ. 2. Determining the endurance of the convergent-accommodative apparatus of the eye is advisable for assessing the effectiveness of exercises aimed at improving the functional ability of the visual organ. 3. Applying muscle express relaxation to alleviate 60-minute ocular apparatus overload with palming according to the method of M. Norbekov has a 50 per cent positive effect.4. The effectiveness of applying the proposed relaxation exercises depends on the level of endurance of the visual apparatus