Diffuse type of gastric cancer (GC) has an increasing prevalence worldwide, especially in Western countries, is usually diagnosed at advanced stages, and has no efficacious treatment options. Epidemiological studies have reported an increased mortality from GC after occupational exposure to well-studied pro-carcinogen that are metabolically activated by Cyp P450 enzymes through aryl hydrocarbon receptor (AhR). Substantial studies support the involvement of AhR in gastric carcinogenesis. However, little is known about the role of AhR in diffuse GC, as compared to intestinal GC. In a cohort of 29 gastric tumors, we described a significantly increased AhR protein and mRNA expression levels in GCs, independently of subtypes and clinical parameters. AhR and RhoA mRNA expression were correlated in diffuse GC. Further, our study characterized how AhR affects gene expression in diffuse GC. Using qRT-PCR, we compared the expression levels of AhR, Cyp1A1 and Cyp1B1 to the expression of genes in a panel previously described. In diffuse GC, Cyp1A1 expression correlated with genes involved in IGF signalling, EMT (VIM), migration (MMP2). In an in vitro assay using the poorly differentiated KATOIII epithelial cell line, two well-known ligands for AhR (TCDD and BaP) induced mRNA expression of CYP1A1, IL1b, as well as UGT1, NQO1 and AhRR to a lower extent. We also observed a strong increase in Cyp1B1 expression in diffuse GC, along with a lower TCDD-increased Cyp1B1 expression as compared to Cyp1A1 in KATOIII cells, and immunostaining in stromal cells. In intestinal GC, Cyp1B1 inversely correlated with several genes including IDO1 (generating endogenous kynurenin-e AhR ligand). Our data provide evidence for a major role of AhR in GC, as an environmental xenobiotics receptor, through different mechanisms and pathways in diffuse and intestinal GC. Our results support continued efforts to clarify the identities of exogenous AhR ligands in diffuse GC in order to define new therapeutic strategies.

Background: Fullerenes and metallofullerenes can be considered promising nanopharmaceuticals themselves and as a basis for chemical modification. As reactive oxygen species homeostasis plays a vital role in cells, the study of their effect on genes involved in oxidative stress and anti-inflammatory response is of particular importance. Methods: Human fetal lung fibroblasts were incubated with aqueous dispersions of C60, C70, and Gd@C82 in concentrations of 5 nM and 1.5 µM for 1, 3, 24, and 72 hours. Cell viability, intracellular ROS, NOX4, NFκB, PRAR-γ, NRF2, heme oxygenase 1, and NAD(P)H quinone dehydrogenase 1 expression have been studied. Results & conclusion: The aqueous dispersions of C60, C70, and Gd@C82 fullerenes are active participants in ROS homeostasis. Low and high concentrations of AFDs have similar effects. C70 was the most inert substance, C60 was the most active substance. All AFDs have both a “prooxidant” and “antioxidant” effect, but with a different balance. Gd@C82 was a substance with more pronounced antioxidant and anti-inflammatory properties, while C70 had more pronounced “prooxidant” properties.

Following Smolin, we proceed to unification of general relativity and quantum theory by operating solely with events, i.e., without appealing to physical systems and space-time. The universe is modelled as a dendrogram (finite tree) expressing the hierarchic relations between events. This is the observational (epistemic) model; the ontic model is based on p-adic numbers (infinite trees). Hence, we use novel mathematics—not only space-time but even real numbers are not in use. Here, the p-adic space (which is zero dimensional) serves as the base for the holographic image of the universe. In this way our theory relates to p-adic physics; in particular, p-adic string theory and complex disordered systems (p-adic representation of Parisi matrix for spin glasses). Our Dendrogramic-Holographic (DH) theory matches perfectly with the Mach’s principle and Brans-Dicke theory. We found surprising informational interrelation between the fundamental constants, h, c, G, and their DH-analogues, h(D), c(D), G(D). DH-theory is part of Wheeler’s project on the information restructuring of physics. It is also a step towards the Unified Field theory. The universal potential V is nonlocal, but this is relational DH-nonlocality. V can be coupled to the Bohm quantum potential by moving to the real representation. This coupling enhanced the role of the Bohm potential.

At the molecular level, aging is often accompanied by dysfunction of stress-induced membrane-less organelles (MLOs) and changes in their material state. In this work, we analyzed the proteins included in the proteome of stress granules (SGs) and P-bodies for their tendency to transform the material state of these MLOs. Particular attention was paid to proteins whose gene expression changes during replicative aging. It was shown that the proteome of the studied MLOs practically does not differ in the analyzed characteristics and consists of completely or partially intrinsically disordered proteins, 30 - 40% of which are potentially capable of liquid-liquid phase separation (LLPS). At the same time, the proportion of proteins capable of spontaneous LLPS is relatively small, which indicates the leading role of nucleic acids in the biogenesis of these membrane-less organelles. Proteins whose gene expression changes during the transition of human cells to a senescent state make up about 20% of the studied proteomes. There is a statistically significant increase in the number of positively charged proteins in both datasets studied compared to the complete proteomes of these organelles. An increase in the relative content of DNA-, but not RNA-binding proteins, was also found in the stress-granules dataset with senescence-related processes. Among SG proteins potentially involved in senescent processes, there is an increase in the abundance of potentially amyloidogenic proteins compared to the whole proteome. The hnRPDL protein has the highest degree of disorder and highest propensity for LLPS among such proteins, which allows us to consider it as “potentially dangerous.” Proteins common to SGs and P bodies, potentially involved in processes associated with senescence, form clusters of interacting proteins. The largest cluster is represented by RNA-binding proteins involved in RNA processing and translation regulation. These data indicate that SG proteins, but not proteins of P-bodies, are more likely to transform the material state of MLOs. Furthermore, these MLOs can participate in processes associated with aging in a coordinated manner.

Alzheimer's disease (AD) is the most prevalent form of dementia. With the global aging population, the incidence of AD and related dementias is projected to rise dramatically, posing significant public health challenges. Traditionally, the diagnosis of AD has relied on the detection of amyloid-beta (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau in the brain, assessed through invasive cerebrospinal fluid (CSF) analysis and costly positron emission tomography scans. However, these methods are not feasible for widespread screening or use in low-resource settings. Recent advances in blood-based biomarkers offer a promising alternative for the early detection and monitoring of AD. These biomarkers provide a minimally invasive, cost-effective means of tracking the pathological progression of AD before the onset of clinical symptoms, potentially enabling earlier and more accurate diagnosis. Blood-based biomarkers, including those related to Aβ, phosphorylated tau, and neurofilament light polypeptide, have demonstrated significant potential in reflecting the underlying neuropathology of AD and correlating with traditional CSF and imaging biomarkers. This review synthesizes the latest research on blood-based biomarkers in AD, highlighting their role in the disease's etiopathogenesis, diagnostic accuracy, and prognostic value. We discuss the emerging evidence on proteinopathies, neuroinflammation, vascular pathology, and bioenergetic profiles, emphasizing the clinical applicability of these biomarkers. Furthermore, we explore the integration of blood-based biomarkers with advanced neuroimaging techniques and their potential to revolutionize the diagnostic landscape of AD, particularly in resource-limited settings. We have integrated protein-protein interaction (PPI) and miRNA network analyses to enhance the analysis. By incorporating these, we can explore the interactions and relationships between different proteomic, genomic, and epigenomic biomarkers, potentially unveiling new insights into the underlying biological mechanisms of AD. The continued development and validation of these biomarkers could lead to more accessible and equitable AD diagnostics, ultimately improving patient outcomes.

In this paper we introduce the New/Generalized two parameter Gamma function and Pochhammer symbol. We named them, as Generalized p - k Gamma Function and Generalized p - k Pochhammer symbol and denoted as $ _{p}^{a}\Gamma_{k}(x) $ and $ _{p}^{a}(x)_{n,k} $ respectively. We prove the several identities for $ _{p}^{a}\Gamma_{k}(x) $ and $ _{p}^{a}(x)_{n,k} $ those satisfied by the classical Gamma function. Also we provide the integral representation for the $ _{p}^{a}\Gamma_{k}(x) $

Nodule bacteria (rhizobia) represent a suitable model to address a range of evolutionary prob-lems including the tradeoff between genetic polymorphism and natural selection. Rhizobia possess the complicated genomes in which symbiotically specialized (sym) genes differ in their natural histories from core genes encoding for housekeeping functions. Diversification of sym genes is responsible for the rhizobia microevolution which depends on the host-induced natural selection. For the rhizobia speciation, diversification of core genes is responsible for which the selective factors are unclear. In this paper we demonstrate that in the goats’ rue rhizobia (Neorhizobium galegae) populations collected at North Caucasus and composed of two host-specific biovars orientalis and officianalis (N2-fixing symbionts of Galega orientalis and G. officinalis, respectively), evolutionary mechanisms are different for core and sym genes. In both N. galegae biovars, core genes are more polymorphic than sym genes. In bv. orientalis, evolution of core genes occurs under the impacts of driving se-lection (dN/dS > 1), while evolution of sym genes is close to neutral (dN/dS ≈ 1). In bv. officinalis, evolution of core genes is neutral, while for sym genes, it is dependent on purifying selection (dN/dS < 1). A marked phylogenetic congruence of core and sym genes revealed using the ANI analysis may be due to a low intensity of gene transfer within and between N. galegae biovars. Polymorphism of both gene groups and the impacts of driving selection on the core gene evolu-tion are more pronounced in bv. orientalis than in bv. officianalis reflecting the diversities of re-spective host plant species. In bv. orientalis, highly significant (P0 < 0,001) positive correlation was revealed between the p-distance and dN/dS values for core genes, while in bv. officinalis this cor-relation is lowly significant (0,05 < P0 < 0,10). For sym genes, correlation between the p-distance and dN/dS values is negative in bv. officinalis but is not revealed in bv. orientalis. These data along with the functional annotation of core genes implemented using the Gene Ontology tools sug-gests that evolution of bv. officinalis is based mostly on adaptation for in planta niches while in bv. orientalis evolution presumable depends on adaptation for soil niches. New insights into the tradeoff between natural selection and genetic diversity are presented suggesting that the gene polymorphism may be extended by driving selection only in the ecologically versatile organ-isms capable to support a broad spectrum of gene alleles in their genepools.

Antimicrobial peptides provide a powerful toolkit for combating multidrug resistance. Combatting eukaryotic pathogens is complicated by the fact, the intracellular drug targets in the eukaryotic pathogen are frequently homologs of cellular structures of vital importance in the host organism. The entomopathogenic bacteria, (symbionts of entomopathogenic nematode species), release a series of non-ribosomal templated antimicrobial peptides, some may be potential drug candidates. The ability of an entomopathogenic nematode /entomopathogenic bacterium symbiotic complex to survive in a given polyxenic milieu is a coevolutionary product, explaining that those gene complexes which are responsible for the biosynthesis of different non-ribosomal templated antimicrobial protective peptides (including those which are potently capable to inactivate the protist mammalian -pathogen Leishmania and the gallinaceous bird pathogen Histomonas) are co-regulated. Our approach is based on comparative antimicrobial bioassays of the culture media of the wild-type and regulatory mutant strains. We concluded that Xenorhabdus budapestensis and X. szentirmaii are excellent sources of non-ribosomal templated antimicrobial peptides, that are efficient antagonists of the mentioned pathogens. Data on selective cytotoxicity of different cell-free culture media encourages us to forecast that the recently discovered “easy-PACId” research strategy is suitable for constructing EPB strains producing and releasing single, harmless, non-ribosomal templated antimicrobial peptides with considerable drug, (probiotic) -candidate potential.