Functional Differentiation Research Articles

MRNA-1273 vaccination induces polyfunctional memory CD4 and CD8 T cell responses in patients with solid cancers undergoing immunotherapy or/and chemotherapy.

Research has confirmed the safety and comparable seroconversion rates following SARS-CoV-2 vaccination in patients with solid cancers. However, the impact of cancer treatment on vaccine-induced T cell responses remains poorly understood. In this study, we expand on previous findings within the VOICE trial by evaluating the functional and phenotypic composition of mRNA-1273-induced T cell responses in patients with solid tumors undergoing immunotherapy, chemotherapy, or both, compared to individuals without cancer. We conducted an ELISpot analysis on 386 participants to assess spike-specific T cell responses 28 days after full vaccination. Further in-depth characterization of using flow cytometry was performed on a subset of 63 participants to analyze the functional phenotype and differentiation state of spike-specific T cell responses. ELISpot analysis showed robust induction of spike-specific T cell responses across all treatment groups, with response rates ranging from 75% to 80%. Flow cytometry analysis revealed a distinctive cytokine production pattern across cohorts, with CD4 T cells producing IFNγ, TNF, and IL-2, and CD8 T cells producing IFNγ, TNF, and CCL4. Variations were observed in the proportion of monofunctional CD4 T cells producing TNF, particularly higher in individuals without cancer and patients treated with chemotherapy alone, while those treated with immunotherapy or chemoimmunotherapy predominantly produced IFNγ. Despite these differences, polyfunctional spike-specific memory CD4 and CD8 T cell responses were comparable across cohorts. Notably, immunotherapy-treated patients exhibited an expansion of spike-specific CD4 T cells with a terminally differentiated effector memory phenotype. These findings demonstrate that systemic treatment in patients with solid tumors does not compromise the quality of polyfunctional mRNA-1273-induced T cell responses. This underscores the importance of COVID-19 vaccination in patients with solid cancers undergoing systemic treatment.

Формирование «новой зрелищности». Как устроен современный стриминг (на примере Netflix и др.)

The paper aims to identify the characteristics of the “new spectacle” in the context of screen digitization. The author’s focus on identifying the stages of screen digitization and the emergence of new cultural practices when viewing content on streaming services is crucial. The scientific novelty of the study lies in its multifaceted analysis of media consumption and media production transformations in the digital age, particularly emphasizing the significant role of streaming services in these processes. The author investigates the interactive aspects of streaming services where viewers can influence the plot, which is a significant contribution to understanding contemporary media practices. As a result, the author emphasizes that streaming services have become catalysts for numerous changes in the media industry, leading to democratization of content access and production. The work notes the possibility of a functional differentiation of modern media consumption culture under the influence of screen culture before the streaming era and during the streaming era. The emergence of new demands for content creation in the context of the “new spectacle” is highlighted.

Gene Duplication and Functional Diversification of MADS-Box Genes in Malus × domestica following WGD: Implications for Fruit Type and Floral Organ Evolution.

The evolution of the MADS-box gene family is essential for the rapid differentiation of floral organs and fruit types in angiosperms. Two key processes drive the evolution of gene families: gene duplication and functional differentiation. Duplicated copies provide the material for variation, while advantageous mutations can confer new functions on gene copies. In this study, we selected the Rosaceae family, which includes a variety of fruit types and flower organs, as well as species that existed before and after whole-genome duplication (WGD). The results indicate that different fruit types are associated with different copies of MADS-box gene family duplications and WGD events. While most gene copies derived from WGD have been lost, MADS-box genes not only retain copies derived from WGD but also undergo further gene duplication. The sequences, protein structures, and expression patterns of these gene copies have undergone significant differentiation. This work provides a clear example of MADS-box genes in the context of gene duplication and functional differentiation, offering new insights into the evolution of fruit types and floral organs.

The biological effects of Rosa rugosa extract on keratinocyte differentiation and enhancement of skin barrier function

The biological effects of Rosa rugosa extract on keratinocyte differentiation and enhancement of skin barrier function

Revisiting the Immunometabolic Basis for the Metabolic Syndrome from an Immunonutritional View.

Metabolic syndrome (MetS) implies different conditions where insulin resistance constitutes a major hallmark of the disease. The disease incurs a high risk for the development of cardiovascular complications, and takes its toll in regard to the gut-liver axis (pancreas, primary liver and colorectal)-associated immunity. The modulation of immunometabolic responses by immunonutritional factors (IFs) has emerged as a key determinant of the gut-liver axis' metabolic and immune health. IFs from plant seeds have shown in vitro and pre-clinical effectiveness primarily in dealing with various immunometabolic and inflammatory diseases. Only recently have immunonutritional studies established the engagement of innate intestinal immunity to effectively control immune alterations in inflamed livers preceding the major features of the MetS. However, integrative analyses and the demonstration of causality between IFs and specific gut-liver axis-associated immunometabolic imbalances for the MetS remain ill-defined in the field. Herein, a better understanding of the IFs with a significant role in the MetS, as well as within the dynamic interplay in the functional differentiation of innate immune key effectors (i.e., monocytes/macrophages), worsening or improving the disease, could be of crucial relevance. The development of an adequate intermediary phenotype of these cells can significantly contribute to maintaining the function of Tregs and innate lymphoid cells for the prevention and treatment of MetS and associated comorbidities.

Diversity and functional differentiation of renewal buds in temperate herbaceous plants.

Spring regrowth in temperate perennials relies on renewal buds, which form a key component in the shoot growth cycle. Still, we possess almost no information on these renewal buds, which is becoming more pressing with the current climate change. Most existing studies concentrated on easy-to-study aboveground buds of woody plants, whose morphology has largely been linked to frost protection. It is not clear to what extent these findings apply also to herbaceous species. We therefore examined protective traits and preformation of winter renewal buds in 379 species of temperate herbs, and tested how these traits are distributed across the phylogeny and related to other bud bank and whole-plant traits. We identified a major gradient from few, large, highly preformed, scale-covered buds associated with larger belowground storage organs deep in the soil, to small, numerous, less preformed, and naked buds near the soil surface. Belowground renewal buds of temperate herbs show several distinct strategies for winter survival and spring regrowth that might affect their response to changing winter and early spring conditions. Renewal bud traits are driven not only by frost protection but also by protection of the apical meristem from mechanical disturbance in the soil.

On locally Lipschitz convex functions defined on subsets with empty interior of locally convex spaces

The generic Fréchet and/or Gateaux differentiability of a continuous convex function on an open convex subset of a Banach space is well studied and has important theoretical implications. An example of Rainwater [Yet more on the differentiability of convex functions. Proc Amer Math Soc. 1988;103(3):773–778] shows that similar results are not true when the openness of the domain is not ensured, but such properties can be obtained if the respective convex function is assumed to be locally Lipschitz, as shown by Verona [More on the differentiability of convex functions. Proc Amer Math Soc. 1988;103(1):137–140]; Rainwater [Yet more on the differentiability of convex functions. Proc Amer Math Soc. 1988;103(3):773–778]; Noll [Generic Gâteaux-differentiability of convex functions on small sets. J Math Anal Appl. 1990;147(2):531–544] and others. It is our aim to extend such results for convex functions defined on (not necessarily open) convex subsets of locally convex spaces. In the same framework we extend Gale's duality theorem (1967), as well as a result of H. Ergin & T. Sarver on the unique dual representation of a convex function (2010). Moreover, a detailed study of the Rainwater example is done.

Adaptive Evolution and Functional Differentiation of Testis-Expressed Genes in Theria.

Gene expression patterns differ in different tissues, and the expression pattern of genes in the mammalian testis is known to be extremely variable in different species. To clarify how the testis transcriptomic pattern has evolved in particular species, we examined the evolution of the adult testis transcriptome in Theria using 10 species: two marsupials (opossum and Tasmanian devil), six eutherian (placental) mammals (human, chimpanzee, bonobo, gorilla, rhesus macaque, and mouse), and two outgroup species (platypus and chicken). We show that 22 testis-expressed genes are marsupial-specific, suggesting their acquisition in the stem lineage of marsupials after the divergence from eutherians. Despite the time length of the eutherian stem lineage being similar to that of the marsupial lineage, acquisition of testis-expressed genes was not found in the stem lineage of eutherians; rather, their expression patterns differed by species, suggesting rapid gene evolution in the eutherian ancestors. Fifteen testis-expressed genes are therian-specific, and for three of these genes, the evolutionary tempo is markedly faster in eutherians than in marsupials. Our phylogenetic analysis of Rho GTPase-activating protein 28 (ARHGAP28) suggests the adaptive evolution of this gene in the eutherians, probably together with the expression pattern differentiation.

The active form of vitamin D (calcitriol) promotes CXCR5 expression during follicular helper T cell differentiation.

Follicular helper T (Tfh) cells promote B cell differentiation and antibody production in the B cell follicles of secondary lymphoid organs. Tfh cells express their signature transcription factor BCL6, interleukin (IL)-21, and surface molecules including inducible T cell costimulator, programmed cell death-1 (PD-1), and the chemokine receptor CXCR5. Migration of Tfh cells to B cell follicles largely depends on the CXCR5 expression induced by interactions with antigen-presenting dendritic cells in the T cell area. How Tfh cells acquire sufficient levels of CXCR5 expression, however, has remained unclear. Using our in vitro culture system to generate CXCR5low Tfh-like cells from naïve CD4+ T cells with IL-6 in the absence of other cell types, we found that the active form of vitamin D, calcitriol, markedly enhanced CXCR5 expression after the release from persistent T cell receptor (TCR) stimulation. CH-223191, an aryl hydrocarbon receptor antagonist, further enhanced CXCR5 expression. IL-12 but not IL-4, in place of IL-6, also supported calcitriol to enhance CXCR5 expression even before the release from TCR stimulation, whereas the cell viability sharply decreased after the release. The Tfh-like cells generated with IL-6 and calcitriol exhibited chemotaxis towards CXCL13, expressed IL-21, and helped B cells to produce IgG antibodies in vitro more efficiently than Tfh-like cells generated without added calcitriol. Calcitriol injections into antigen-primed mice increased the proportion of CXCR5+PD-1+CD4+ cells in their lymphoid organs, and enhanced T cell entry into B-cell follicles. These results suggest that calcitriol promotes CXCR5 expression in developing Tfh cells and regulates their functional differentiation.

Модификация модели прогнозирования финансово-экономического состояния для задачи управления развитием медицинских учреждений

The article analyzes the model of forecasting the financial and economic condition, considers the possibility of its transformation for managing the development of medical institutions, and provides an appropriate modification using methods of discriminant analysis and mathematical programming. The formulated modification of the model has a clear mathematical justification, which allows, on the one hand, to prove its validity, and on the other hand constructively shows the possibility of its use, taking into account the specifics of the medical industry. The purpose of the work. The purpose of this work is to study changes in the forecasting model of the financial and economic condition, taking into account the specifics of the industry, as well as to evaluate the application of methods of discriminant analysis, reducing them to a mathematical programming problem, the limitations of which are reduced to systems of linear inequalities obtained by building maximally joint subsystems. Materials and methods. It is proposed to use the method of discriminant analysis with extensible precedent sets. It is assumed that in order to improve the quality of solving this problem, expert judgments about objects that were not initially included in the training sample are involved. At the same time, the goal is to determine the best objects to involve them in the learning material in order to maximize the solution of the problem. To formalize the model based on the predicted values, we will encrypt all available data into a vector of states. The considered methods show their effectiveness. The results of the study. During the modification of the economic and financial condition model, a conclusion is made about the linearization of the model, which is also associated with the differentiation operation. The possibility of using neural networks is also demonstrated for the case of differentiation of complex functions, and in the case of convex programming, for marginal estimates obtained using the directional differentiation operation. Conclusion. The results obtained allow us to assert that the use of strict mathematical tools, a modified model of the economic and financial condition for the medical industry is easy to use for development management, since it can be implemented as some component of a computer program (neural network) into which the administrator enters data, and at the output receives a processed result.

Microbial communities reveal niche partitioning across the slope and bottom zones of the challenger deep.

Widespread marine microbiomes exhibit compositional and functional differentiation as a result of adaptation driven by environmental characteristics. We investigated the microbial communities in both seawater and sediments on the slope (7-9 km) and the bottom (9-11 km) of the Challenger Deep of the Mariana Trench to explore community differentiation. Both metagenome-assembled genomes (MAGs) and 16S rRNA amplicon sequence variants (ASVs) showed that the microbial composition in the seawater was similar to that of sediment on the slope, while distinct from that of sediment in the bottom. This scenario suggested a potentially stronger community interaction between seawater and sediment on the slope, which was further confirmed by community assembly and population movement analyses. The metagenomic analysis also indicates a specific stronger potential of nitrate reduction and sulphate assimilation in the bottom seawater, while more versatile nitrogen and sulphur cycling pathways occur on the slope, reflecting functional differentiations among communities in conjunction with environmental features. This work implies that microbial community differentiation occurred in the different hadal niches, and was likely an outcome of microbial adaptation to the extreme hadal trench environment, especially the associated hydrological and geological conditions, which should be considered and measured in situ in future studies.

Differential reorganization of episodic and semantic memory systems in epilepsy-related mesiotemporal pathology.

Declarative memory encompasses episodic and semantic divisions. Episodic memory captures singular events with specific spatiotemporal relationships, while semantic memory houses context-independent knowledge. Behavioural and functional neuroimaging studies have revealed common and distinct neural substrates of both memory systems, implicating mesiotemporal lobe (MTL) regions such as the hippocampus and distributed neocortices. Here, we explored declarative memory system reorganization in patients with unilateral temporal lobe epilepsy (TLE) as a human disease model to test the impact of variable degrees of MTL pathology on memory function. Our cohort included 31 patients with TLE as well as 60 age and sex-matched healthy controls, and all participants underwent episodic and semantic retrieval tasks during a multimodal MRI session. The functional MRI tasks were closely matched in terms of stimuli and trial design. Capitalizing on non-linear connectome gradient mapping techniques, we derived task-based functional topographies during episodic and semantic memory states, both in the MTL and in neocortical networks. Comparing neocortical and hippocampal functional gradients between TLE patients and healthy controls, we observed a marked topographic reorganization of both neocortical and MTL systems during episodic memory states. Neocortical alterations were characterized by reduced functional differentiation in TLE across lateral temporal and midline parietal cortices in both hemispheres. In the MTL, on the other hand, patients presented with a more marked functional differentiation of posterior and anterior hippocampal segments ipsilateral to the seizure focus and pathological core, indicating perturbed intrahippocampal connectivity. Semantic memory reorganization was also found in bilateral lateral temporal and ipsilateral angular regions, while hippocampal functional topographies were unaffected. Leveraging MRI proxies of MTL pathology, we furthermore observed alterations in hippocampal microstructure and morphology that were associated with TLE-related functional reorganization during episodic memory. Moreover, correlation analysis and statistical mediation models revealed that these functional alterations contributed to behavioural deficits in episodic, but again not semantic memory in patients. Altogether, our findings suggest that semantic processes rely on distributed neocortical networks, while episodic processes are supported by a network involving both the hippocampus and neocortex. Alterations of such networks can provide a compact signature of state-dependent reorganization in conditions associated with MTL damage, such as TLE.

Human microglia-derived proinflammatory cytokines facilitate human retinal ganglion cell development and regeneration

Microglia (μG), the resident immune cells in the central nervous system, surveil the parenchyma to maintain the structural and functional homeostasis of neurons. Besides, they influence neurogenesis and synaptogenesis through complement-mediated phagocytosis. Emerging evidence suggests that μG may also influence development through proinflammatory cytokines. Here, we examined the premise that tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β), the two most prominent components of the μG secretome, influence retinal development, specifically the morphological and functional differentiation of human retinal ganglion cells (hRGCs). Using controlled generation of hRGCs and human μG (hμG) from pluripotent stem cells, we demonstrate that TNF-α and IL-1β secreted by unchallenged hμG did not influence hRGC generation. However, their presence significantly facilitated neuritogenesis along with the basal function of hRGCs, which involved the recruitment of the AKT/mTOR pathway. We present exvivo evidence that proinflammatory cytokines may play an important role in the morphological and physiological maturation of hRGCs, which may be recapitulated for regeneration.

Ag-driven CD8+ T cell clonal expansion is a prominent feature of MASH in humans and mice.

Chronic liver disease due to metabolic dysfunction-associated steatohepatitis (MASH) is a rapidly increasing global epidemic. MASH progression is a consequence of the complex interplay between inflammatory insults and dysregulated hepatic immune responses. T lymphocytes have been shown to accumulate in the liver during MASH, but the cause and consequence of T cell accumulation in the liver remain unclear. Our study aimed to define the phenotype and T cell receptor diversity of T cells from human cirrhotic livers and an animal model of MASH to begin resolving their function in disease. In these studies, we evaluated differences in T cell phenotype in the context of liver disease. Accordingly, we isolated liver resident T cell populations from humans with cirrhosis and from mice with diet-induced MASH. Using both 5' single-cell sequencing and flow cytometry, we defined the phenotype and T cell receptor repertoire of liver resident T cells during health and disease. MASH-induced human cirrhosis and diet-induced MASH in mice resulted in the accumulation of activated and clonally expanded T cells in the liver. The clonally expanded T cells in the liver expressed markers of chronic antigenic stimulation, including PD1, TIGIT, and TOX. Overall, this study establishes for the first time that T cells undergo Ag-dependent clonal expansion and functional differentiation during the progression of MASH. These studies could lead to the identification of antigenic targets that drive T cell activation, clonal expansion, and recruitment to the liver during MASH.

Photoacoustic imaging for three-dimensional bioprinted constructs

Bioimaging is used to inspect the successful growth and functional differentiation of cells in printed biomaterials, which are ultimately finalized into functional artificial tissues capable of replacing native tissues. While optical bioimaging techniques are commonly utilized, the current trend in three-dimensional (3D) bioprinting towards replicating complex 3D microarchitectures poses a challenge for conventional optical imaging techniques in providing clear cross-sectional images due to the opaque nature of tissue. Consequently, these limitations necessitate lengthy and destructive preparation processes, which are associated with sacrificing cell viability and damaging the bioprinted material. Photoacoustic imaging (PAI) is a versatile imaging technique that extends the advantages of the optical bioimaging technique to undiscovered depths enabled by its acoustic hybridity, making itself a promising tool for non-destructive imaging of 3D bioprinted constructs. In this review, we introduce the flexible spectral contrasts provided by PAI, which are potentially applicable to 3D-bioprinted constructs, and summarize bioprinting studies that functionally implement PAI for in vitro and in vivo assessments. Finally, we provide an outlook on practical considerations for the more complete integration of these two fields, anticipating more fruitful discoveries as bioprinting advances towards more complex hierarchies.

Genome-wide identification, phylogenetic, structural and functional evolution of thecore components of ABA signaling in plant species: a focus on rice.

A genome-wide analysis had identified 642 ABA core component genes from 20 plant species, which were further categorized into three distinct subfamilies. The gene structures and evolutionary relationships of these genes had been characterized. PP2C_1, PP2C_2, and SnRK2_1 had emerged as key players in mediating the ABA signaling transduction pathway, specifically in rice, in response to abiotic stresses. The plant hormone abscisic acid (ABA) is essential for growth, development, and stress response, relying on its core components, pyrabactin resistance, pyrabactin resistance-like, and the regulatory component of ABA receptor (PYR/PYL/RCAR), 2C protein phosphatase (PP2C), sucrose non-fermenting-1-related protein kinase 2 (SnRK2). However, there's a lack of research on their structural evolution and functional differentiation across plants. Our study analyzed the phylogenetic, gene structure, homology, and duplication evolution of this complex in 20 plant species. We found conserved patterns in copy number and homology across subfamilies. Segmental and tandem duplications drove the evolution of these genes, while whole-genome duplication (WGD) expanded PYR/PYL/RCAR and PP2C subfamilies, enhancing environmental adaptation. In rice and Arabidopsis, the PYR/PYL/RCAR, PP2C, and SnRK2 genes showed distinct tissue-specific expression and responded to various stresses. Notably, PP2C_1 and PP2C_2 interacted with SnRK2_1 and were crucial for ABA signaling in rice. These findings offered new insights into ABA signaling evolution, interactions, and integration in green plants, benefiting future research in agriculture, evolutionary biology, ecology, and environmental science.

On differentiability of Sobolev functions with respect to the Sobolev norm

AbstractWe study connections between the ‐differentiability and the ‐differentiability of Sobolev functions. We prove that ‐differentiability implies the ‐differentiability, but the opposite implication is not valid. The notion of approximate differentiability is discussed as well. In addition, we consider the ‐differentiability of Sobolev functions ‐almost everywhere.

Smoothness of Generalized Solutions to the Dirichlet Problem for Strongly Elliptic Functional Differential Equations with Orthotropic Contractions on the Boundary of Adjacent Subdomains

Smoothness of Generalized Solutions to the Dirichlet Problem for Strongly Elliptic Functional Differential Equations with Orthotropic Contractions on the Boundary of Adjacent Subdomains

Genome-Wide Identification and Characterization of CCT Gene Family from Microalgae to Legumes.

The CCT (CO, COL and TOC1) gene family has been elucidated to be involved in the functional differentiation of the products in various plant species, but their specific mechanisms are poorly understood. In the present investigation, we conducted a genome-wide identification and phylogenetic analysis of CCT genes from microalgae to legumes. A total of 700 non-redundant members of the CCT gene family from 30 species were identified through a homology search. Phylogenetic clustering with Arabidopsis and domain conservation analysis categorized the CCT genes into three families. Multiple sequence alignment showed that the CCT domain contains important amino acid residues, and each CCT protein contains 24 conserved motifs, as demonstrated by the motif analysis. Whole-genome/segment duplication, as well as tandem duplication, are considered to be the driving forces in the evolutionary trajectory of plant species. This comprehensive investigation into the proliferation of the CCT gene family unveils the evolutionary dynamics whereby WGD/segment duplication is the predominant mechanism contributing to the expansion of the CCT genes. Meanwhile, the examination of the gene expression patterns revealed that the expression patterns of CCT genes vary in different tissues and at different developmental stages of plants, with high expression in leaves, which is consistent with the molecular regulation of flowering in photosynthesis by CCT. Based on the protein-protein interaction analysis of CCT genes in model plants, we propose that the CCT gene family synergistically regulates plant development and flowering with light-signaling factors (PHYs and PIFs) and MYB family transcription factors. Understanding the CCT gene family's molecular evolution enables targeted gene manipulation for enhanced plant traits, including optimized flowering and stress resistance.

Combined effects of climate and land-use changes on the alpha and beta functional diversities of terrestrial mammals in China.

Climate and land-use changes are predicted to impact biodiversity, threatening ecosystem services and functions. However, their combined effects on the functional diversity of mammals at the regional scale remain unclear, especially at the beta level. Here, we use projected climate and land-use changes in China to investigate their potential effects on the alpha and beta functional diversities of terrestrial mammals under low- and high-emission scenarios. In the current projection, we showed strong positive spatial correlations between functional richness and species richness. Functional evenness (FEve), functional specialization (FSpe), and functional originality (FOri) decreased with species richness, and functional divergence (FDiv) increased first and then plateaued. Functional beta diversity was dominated by its nestedness component, in contrast to the taxonomic facet. Potential changes in species richness are more strongly influenced by land-use change under the low-emission scenario, while under the high-emission scenario, they are more strongly influenced by climate change. Changes in functional richness (FRic) were inconsistent with those in species richness, with a magnitude of decreases greater than predicted from species richness. Moreover, mammal assemblages showed potential functional differentiation (FD) across the country, and the trends exceeded those towards taxonomic differentiation (TD). Our findings help us understand the processes underlying biodiversity responses to global changes on multiple facets and provide new insight for conservation plans.