Regulatory Link Research Articles

The ChvG-ChvI and NtrY-NtrX Two-Component Systems Coordinately Regulate Growth of Caulobacter crescentus.

Two-component signaling systems (TCSs) are comprised of a sensory histidine kinase and a response regulator protein. In response to environmental changes, sensor kinases directly phosphorylate their cognate response regulator to affect gene expression. Bacteria typically express multiple TCSs that are insulated from one another and regulate distinct physiological processes. There are examples of cross-regulation between TCSs, but this phenomenon remains relatively unexplored. We have identified regulatory links between the ChvG-ChvI (ChvGI) and NtrY-NtrX (NtrYX) TCSs, which control important and often overlapping processes in alphaproteobacteria, including maintenance of the cell envelope. Deletion of chvG and chvI in Caulobacter crescentus limited growth in defined medium, and a selection for genetic suppressors of this growth phenotype uncovered interactions among chvGI, ntrYX, and ntrZ, which encodes a previously uncharacterized periplasmic protein. Significant overlap in the experimentally defined ChvI and NtrX transcriptional regulons provided support for the observed genetic connections between ntrYX and chvGI. Moreover, we present evidence that the growth defect of strains lacking chvGI is influenced by the phosphorylation state of NtrX and, to some extent, by levels of the TonB-dependent receptor ChvT. Measurements of NtrX phosphorylation in vivo indicated that NtrZ is an upstream regulator of NtrY and that NtrY primarily functions as an NtrX phosphatase. We propose a model in which NtrZ functions in the periplasm to inhibit NtrY phosphatase activity; regulation of phosphorylated NtrX levels by NtrZ and NtrY provides a mechanism to modulate and balance expression of the NtrX and ChvI regulons under different growth conditions. IMPORTANCE TCSs enable bacteria to regulate gene expression in response to physiochemical changes in their environment. The ChvGI and NtrYX TCSs regulate diverse pathways associated with pathogenesis, growth, and cell envelope function in many alphaproteobacteria. We used Caulobacter crescentus as a model to investigate regulatory connections between ChvGI and NtrYX. Our work defined the ChvI transcriptional regulon in C. crescentus and revealed a genetic interaction between ChvGI and NtrYX, whereby modulation of NtrYX signaling affects the survival of cells lacking ChvGI. In addition, we identified NtrZ as a periplasmic inhibitor of NtrY phosphatase activity in vivo. Our work establishes C. crescentus as an excellent model to investigate multilevel regulatory connections between ChvGI and NtrYX in alphaproteobacteria.

Data-driven Gene Regulatory Networks Inference Based on Classification Algorithms

Inferring Gene Regulatory Networks from high-throughput gene expression data is a challenging problem, addressed by the systems biology community. Most approaches that aim at unraveling the gene regulation mechanisms in a data-driven way, analyze gene expression datasets to score potential regulatory links between transcription factors and target genes. So far, three major families of approaches have been proposed to score regulatory links. These methods rely respectively on correlation measures, mutual information metrics, and regression algorithms. In this paper we present a new family of data-driven inference methods. This new family, inspired by the regression-based paradigm, relies on the use of classification algorithms. This paper assesses and advocates for the use of this paradigm as a new promising approach to infer gene regulatory networks. Indeed, the development and assessment of five new inference methods based on well-known classification algorithms shows that the classification-based inference family exhibits good results when compared to well-established paradigms.

MMFGRN: a multi-source multi-model fusion method for gene regulatory network reconstruction.

Lots of biological processes are controlled by gene regulatory networks (GRNs), such as growth and differentiation of cells, occurrence and development of the diseases. Therefore, it is important to persistently concentrate on the research of GRN. The determination of the gene-gene relationships from gene expression data is a complex issue. Since it is difficult to efficiently obtain the regularity behind the gene-gene relationship by only relying on biochemical experimental methods, thus various computational methods have been used to construct GRNs, and some achievements have been made. In this paper, we propose a novel method MMFGRN (for "Multi-source Multi-model Fusion for Gene Regulatory Network reconstruction") to reconstruct the GRN. In order to make full use of the limited datasets and explore the potential regulatory relationships contained in different data types, we construct the MMFGRN model from three perspectives: single time series data model, single steady-data model and time series and steady-data joint model. And, we utilize the weighted fusion strategy to get the final global regulatory link ranking. Finally, MMFGRN model yields the best performance on the DREAM4 InSilico_Size10 data, outperforming other popular inference algorithms, with an overall area under receiver operating characteristic score of 0.909 and area under precision-recall (AUPR) curves score of 0.770 on the 10-gene network. Additionally, as the network scale increases, our method also has certain advantages with an overall AUPR score of 0.335 on the DREAM4 InSilico_Size100 data. These results demonstrate the good robustness of MMFGRN on different scales of networks. At the same time, the integration strategy proposed in this paper provides a new idea for the reconstruction of the biological network model without prior knowledge, which can help researchers to decipher the elusive mechanism of life.

Oral biopharmaceutics tools: recent progress from partnership through the Pharmaceutical Education and Research with Regulatory Links collaboration.

To summarise key contributions of the Pharmaceutical Education and Research with Regulatory Links (PEARRL) project (2016-2020) to the optimisation of existing and the development of new biopharmaceutics tools for evaluating the in vivo performance of oral drug products during the development of new drugs and at the regulatory level. Optimised biopharmaceutics tools: Based on new clinical data, the composition of biorelevant media for simulating the fed state conditions in the stomach was simplified. Strategies on how to incorporate biorelevant in vitro data of bio-enabling drug products into physiologically based pharmacokinetic (PBPK) modelling were proposed. Novel in vitro biopharmaceutics tools: Small-scale two-stage biphasic dissolution and dissolution-permeation setups were developed to facilitate understanding of the supersaturation effects and precipitation risks of orally administered drugs. A porcine fasted state simulated intestinal fluid was developed to improve predictions and interpretation of preclinical results using in vitro dissolution studies. Based on new clinical data, recommendations on the design of in vitro methodologies for evaluating the GI drug transfer process in the fed state were suggested. The optimized design of in vivo studies for investigating food effects: A food effect study protocol in the pig model was established which successfully predicted the food-dependent bioavailability of two model compounds. The effect of simulated infant fed state conditions in healthy adults on the oral absorption of model drugs was evaluated versus the fasted state and the fed state conditions, as defined by regulatory agencies for adults. Using PBPK modelling, the extrapolated fasted and infant fed conditions data appeared to be more useful to describe early drug exposure in infants, while extrapolation of data collected under fed state conditions, as defined by regulators for adults, failed to capture in vivo infant drug absorption. Substantial progress has been made in developing an advanced suite of biopharmaceutics tools for streamlining drug formulation screening and supporting regulatory applications. These advances in biopharmaceutics were achieved through networking opportunities and research collaborations provided under the H2020 funded PEARRL project.

Interplay between SMAD2 and STAT5A is a critical determinant of IL-17A/IL-17F differential expression

Interleukins (IL)-17A and F are critical cytokines in anti-microbial immunity but also contribute to auto-immune pathologies. Recent evidence suggests that they may be differentially produced by T-helper (Th) cells, but the underlying mechanisms remain unknown. To address this question, we built a regulatory graph integrating all reported upstream regulators of IL-17A and F, completed by ChIP-seq data analyses. The resulting regulatory graph encompasses 82 components and 136 regulatory links. The graph was then supplemented by logical rules calibrated with original flow cytometry data using naive CD4+ T cells, in conditions inducing IL-17A or IL-17F. The model displays specific stable states corresponding to virtual phenotypes explaining IL-17A and IL-17F differential regulation across eight cytokine stimulatory conditions. Our model analysis points to the transcription factors NFAT2A, STAT5A and SMAD2 as key regulators of the differential expression of IL-17A and IL-17F, with STAT5A controlling IL-17F expression, and an interplay of NFAT2A, STAT5A and SMAD2 controlling IL-17A expression. We experimentally observed that the production of IL-17A was correlated with an increase of SMAD2 transcription, and the expression of IL-17F correlated with an increase of BLIMP-1 transcription, together with an increase of STAT5A expression (mRNA), as predicted by our model. Interestingly, RORγt presumably plays a more determinant role in IL-17A expression as compared to IL-17F expression. In conclusion, we propose the first mechanistic model accounting for the differential expression of IL-17A and F in Th cells, providing a basis to design novel therapeutic interventions in auto-immune and inflammatory diseases.

Pseudomonas Flagella: Generalities and Specificities.

Flagella-driven motility is an important trait for bacterial colonization and virulence. Flagella rotate and propel bacteria in liquid or semi-liquid media to ensure such bacterial fitness. Bacterial flagella are composed of three parts: a membrane complex, a flexible-hook, and a flagellin filament. The most widely studied models in terms of the flagellar apparatus are E. coli and Salmonella. However, there are many differences between these enteric bacteria and the bacteria of the Pseudomonas genus. Enteric bacteria possess peritrichous flagella, in contrast to Pseudomonads, which possess polar flagella. In addition, flagellar gene expression in Pseudomonas is under a four-tiered regulatory circuit, whereas enteric bacteria express flagellar genes in a three-step manner. Here, we use knowledge of E. coli and Salmonella flagella to describe the general properties of flagella and then focus on the specificities of Pseudomonas flagella. After a description of flagellar structure, which is highly conserved among Gram-negative bacteria, we focus on the steps of flagellar assembly that differ between enteric and polar-flagellated bacteria. In addition, we summarize generalities concerning the fuel used for the production and rotation of the flagellar macromolecular complex. The last part summarizes known regulatory pathways and potential links with the type-six secretion system (T6SS).

Enhancer Pleiotropy, Gene Expression, and the Architecture of Human Enhancer-Gene Interactions.

Enhancers are often studied as noncoding regulatory elements that modulate the precise spatiotemporal expression of genes in a highly tissue-specific manner. This paradigm has been challenged by recent evidence of individual enhancers acting in multiple tissues or developmental contexts. However, the frequency of these enhancers with high degrees of “pleiotropy” out of all putative enhancers is not well understood. Consequently, it is unclear how the variation of enhancer pleiotropy corresponds to the variation in expression breadth of target genes. Here, we use multi-tissue chromatin maps from diverse human tissues to investigate the enhancer–gene interaction architecture while accounting for 1) the distribution of enhancer pleiotropy, 2) the variations of regulatory links from enhancers to target genes, and 3) the expression breadth of target genes. We show that most enhancers are tissue-specific and that highly pleiotropy enhancers account for <1% of all putative regulatory sequences in the human genome. Notably, several genomic features are indicative of increasing enhancer pleiotropy, including longer sequence length, greater number of links to genes, increasing abundance and diversity of encoded transcription factor motifs, and stronger evolutionary conservation. Intriguingly, the number of enhancers per gene remains remarkably consistent for all genes (∼14). However, enhancer pleiotropy does not directly translate to the expression breadth of target genes. We further present a series of Gaussian Mixture Models to represent this organization architecture. Consequently, we demonstrate that a modest trend of more pleiotropic enhancers targeting more broadly expressed genes can generate the observed diversity of expression breadths in the human genome.

MiR-320a/SP1 negative reciprocal interaction contributes to cell growth and invasion in colorectal cancer

BackgroundTranscription factors (TFs) may be engaged in reciprocal regulatory circuits with certain miRNAs to maintain cellular homeostasis. Disequilibrium of the reciprocities by certain tumor-related stimuli may give rise to deregulation of downstream cellular signaling pathways, thus promoting malignant tumor phenotypes. Specificity Protein 1 (SP1) is the most representative member of the tumor-related transcription factors. Previous studies disclosed that SP1 can transcriptionally regulate miRNAs and coding genes to facilitate tumor progression. In our study, we used bioinformatic analysis to predict several SP1-binding sites within the miR-320a promoter and found that SP1 is a predicted target gene of miR-320a. Therefore, we hypothesize a reciprocal regulatory link between SP1 and miR-320a that participates in colorectal cancer (CRC) developmentMethodsWe performed bioinformatic analysis, quantitative polymerase chain reaction (qPCR), immunoblotting, dual-luciferase reporter assays, and a series of in vitro and in vivo functional assays to describe a novel SP1/miR-320a reciprocal interaction in CRCResultsFirst, we found that miR-320a was significantly downregulated in CRC tissues and cell lines. Consistent with findings in other cancers, miR-320a exhibited inhibitory effects on cell growth and invasion of CRC in vitro and in vivo. Moreover, we identified SP1 as a target gene of miR-320a, and ectopic SP1 expression partly abolished miR-320a-induced inhibitory effects. Conversely, we confirmed that SP1 interacts with the miR-320a promoter, leading to depression of miR-320a. This illustrates a double-negative feedback loop between miR-320a and SP1. Additionally, based on the fact that SP1 promotes MACC1 transcription, we determined via immunoblotting that the oncogenic MACC1/MET signaling pathway was inactivated in the context of miR-320a-induced SP1 downregulationConclusionTaken together, our study is the first to describe a miR-320a/SP1 negative reciprocal interaction, which contributes to cell growth and invasion in CRC through modulation of the MACC1/MET signaling pathway.

Expression and Functional Assessment of Some Featured Coding and Non-coding RNAs Encoded by 8q24 Chromosomal Region in CML Patients

Background: The association between the human chromosomal 8q24 region and cancer development remains dim. The proto-oncogene MYC is known as the most prominent target of this chromosomal region. However, numerous cancer-associated genetic alterations in the region extend beyond the MYC locus. Accordingly, it is likely that the MYC oncogene is not the only target of these carcinogenesis-related alterations. Objectives: In the present study, the expression of MYC and the correlation between MYC and two non-coding RNAs, namely PVT1 (circular and linear forms) and CASC11, which are residents of the 8q24 region in the MYC neighborhood, were investigated in chronic myeloid leukemia (CML). Methods: Real-time polymerase chain reaction (PCR) was used to assess BCR-ABL transcripts and categorize positive and negative (normal) samples for CML. Afterward, real-time PCR was exploited to evaluate the expression of different genes, including MYC, linear PVT1, circular PVT (CircPVT1), CASC11, and ACTB in CML and normal samples. Results: We found that the expression of linear PVT1 is significantly increased in CML compared with normal samples. However, CircPVT1, CASC11, and MYC did not show significantly altered expression between CML and normal groups. The experimental and in silico analyses of the correlation coefficients of gene expressions suggested changes in the correlations between the gene expressions in CML compared with normal samples. We also assessed the miR-trapping potential of PVT1 and CASC11 and the possible effects of these interactions on signaling pathways. Our findings indicated that these lncRNAs could have a possible regulatory link with critical pathways associated with leukemogenesis. Conclusions: Our results indicate that non-coding genes surrounding MYC within the 8q24 region might have regulatory roles in CML carcinogenesis.

Mechanical instability of adherens junctions overrides intrinsic quiescence of hair follicle stem cells.

Vinculin, a mechanotransducer associated with both adherens junctions (AJs) and focal adhesions (FAs), plays a central role in force transmission through cell-cell and cell-substratum contacts. We generated the conditional knockout (cKO) of vinculin in murine skin that results in the loss of bulge stem cell (BuSC) quiescence and promotes continual cycling of the hair follicles. Surprisingly, we find that the AJs in vinculin cKO cells are mechanically weak and impaired in force generation despite increased junctional expression of E-cadherin and α-catenin. Mechanistically, we demonstrate that vinculin functions by keeping α-catenin in a stretched/open conformation, which in turn regulates the retention of YAP1, another potent mechanotransducer and regulator of cell proliferation, at the AJs. Altogether, our data provide mechanistic insights into the hitherto-unexplored regulatory link between the mechanical stability of cell junctions and contact-inhibition-mediated maintenance of BuSC quiescence.

Development of competence “forecasting” as conditions of readiness for professional self-determination

The article presents the results of the study of the conditionality of the components of forecasting the regulatory-will qualities of the personality among men who are ready and not ready for professional self-determination. In the article, the author reveals the specifics of the competence of forecasting in higher education. In the article, the author identifies two areas in the framework of which the competence of forecasting is considered – as a personal quality and as a "through" skill required in any professional activity. As a result of empirical research, differences were revealed in the conditionality of readiness for professional self-determination, depending on the development of forecasting components. Thus, for students unready for professional self-determination, such components of self-regulation as "planning", "programming", "evaluating results", "flexibility", "independence", are caused by changes in mood, well-being, activity. For students ready for professional self-determination, these same components of self-regulation are determined by the strength of the intentions of young men, the development of volitional qualities, the ability of individual regulation of activity and all regulatory links. Making a conclusion, the author focuses on the role of a teacher at a higher educational organisation in the development of forecasting competence.

BFGF alleviates diabetes-associated endothelial impairment by downregulating inflammation via S-nitrosylation pathway

Protein S-nitrosylation is a reversible protein modification implicated in both physiological and pathophysiological regulation of protein function. However, the relationship between dysregulated S-nitrosylation homeostasis and diabetic vascular complications remains incompletely understood. Here, we demonstrate that basic fibroblast growth factor (bFGF) is a key regulatory link between S-nitrosylation homeostasis and inflammation, and alleviated endothelial dysfunction and angiogenic defects in diabetes. Subjecting human umbilical vein endothelial cells (HUVECs) to hyperglycemia and hyperlipidemia significantly decreased endogenous S-nitrosylated proteins, including S-nitrosylation of inhibitor kappa B kinase β (IKKβC179) and transcription factor p65 (p65C38), which was alleviated by bFGF co-treatment. Pretreatment with carboxy-PTIO (c-PTIO), a nitric oxide scavenger, abolished bFGF-mediated S-nitrosylation increase and endothelial protection. Meanwhile, nitrosylation-resistant IKKβC179S and p65C38S mutants exacerbated endothelial dysfunction in db/db mice, and in cultured HUVECs subjected to hyperglycemia and hyperlipidemia. Mechanistically, bFGF-mediated increase of S-nitrosylated IKKβ and p65 was attributed to synergistic effects of increased endothelial nitric oxide synthase (eNOS) and thioredoxin (Trx) activity. Taken together, the endothelial protective effect of bFGF under hyperglycemia and hyperlipidemia can be partially attributed to its role in suppressing inflammation via the S-nitrosylation pathway.

Toxic stress-specific cytoprotective responses regulate learned behavioral decisions in C. elegans

BackgroundRecognition of stress and mobilization of adequate “fight-or-flight” responses is key for survival and health. Previous studies have shown that exposure of Caenorhabditis elegans to pathogens or toxins simultaneously stimulates cellular stress and detoxification responses and aversive behavior. However, whether a coordinated regulation exists between cytoprotective stress responses and behavioral defenses remains unclear.ResultsHere, we show that exposure of C. elegans to high concentrations of naturally attractive food-derived odors, benzaldehyde and diacetyl, induces toxicity and food avoidance behavior. Benzaldehyde preconditioning activates systemic cytoprotective stress responses involving DAF-16/FOXO, SKN-1/Nrf2, and Hsp90 in non-neuronal cells, which confer both physiological (increased survival) and behavioral tolerance (reduced food avoidance) to benzaldehyde exposure. Benzaldehyde preconditioning also elicits behavioral cross-tolerance to the structurally similar methyl-salicylate, but not to the structurally unrelated diacetyl. In contrast, diacetyl preconditioning augments diacetyl avoidance, weakens physiological diacetyl tolerance, and does not induce apparent molecular defenses. The inter-tissue connection between cellular and behavioral defenses is mediated by JNK-like stress-activated protein kinases and the neuropeptide Y receptor NPR-1. Reinforcement of the stressful experiences using spaced training forms stable stress-specific memories. Memory retrieval by the olfactory cues leads to avoidance of food contaminated by diacetyl and context-dependent behavioral decision to avoid benzaldehyde only if there is an alternative, food-indicative odor.ConclusionsOur study reveals a regulatory link between conserved cytoprotective stress responses and behavioral avoidance, which underlies “fight-or-flight” responses and facilitates self-protection in real and anticipated stresses. These findings imply that variations in the efficiency of physiological protection during past episodes of stress might shape current behavioral decisions.Graphical abstract

FunCoup 5: Functional Association Networks in All Domains of Life, Supporting Directed Links and Tissue-Specificity

FunCoup (https://funcoup.sbc.su.se) is one of the most comprehensive functional association networks of genes/proteins available. Functional associations are inferred by integrating different types of evidence using a redundancy-weighted naïve Bayesian approach, combined with orthology transfer. FunCoup’s high coverage comes from using eleven different types of evidence, and extensive transfer of information between species. Since the latest update of the database, the availability of source data has improved drastically, and user expectations on a tool for functional associations have grown. To meet these requirements, we have made a new release of FunCoup with updated source data and improved functionality. FunCoup 5 now includes 22 species from all domains of life, and the source data for evidences, gold standards, and genomes have been updated to the latest available versions. In this new release, directed regulatory links inferred from transcription factor binding can be visualized in the network viewer for the human interactome. Another new feature is the possibility to filter by genes expressed in a certain tissue in the network viewer. FunCoup 5 further includes the SARS-CoV-2 proteome, allowing users to visualize and analyze interactions between SARS-CoV-2 and human proteins in order to better understand COVID-19. This new release of FunCoup constitutes a major advance for the users, with updated sources, new species and improved functionality for analysis of the networks.

Regulatory Cross Talk between Motility and Interbacterial Communication in Salmonella enterica Serovar Typhimurium.

FliA is a broadly conserved σ factor that directs transcription of genes involved in flagellar motility. We previously identified FliA-transcribed genes in Escherichia coli and Salmonella enterica serovar Typhimurium, and we showed that E. coli FliA transcribes many unstable, noncoding RNAs from intragenic promoters. Here, we show that FliA in S Typhimurium also directs the transcription of large numbers of unstable, noncoding RNAs from intragenic promoters, and we identify two previously unreported FliA-transcribed protein-coding genes. One of these genes, sdiA, encodes a transcription factor that responds to quorum-sensing signals produced by other bacteria. We show that FliA-dependent transcription of sdiA is required for SdiA activity, highlighting a regulatory link between flagellar motility and intercellular communication.IMPORTANCE Initiation of bacterial transcription requires association of a σ factor with the core RNA polymerase to facilitate sequence-specific recognition of promoter elements. FliA is a widely conserved σ factor that directs transcription of genes involved in flagellar motility. We previously showed that Escherichia coli FliA transcribes many unstable, noncoding RNAs from promoters within genes. Here, we demonstrate the same phenomenon in Salmonella Typhimurium. We also show that S Typhimurium FliA directs transcription of the sdiA gene, which encodes a transcription factor that responds to quorum-sensing signals produced by other bacteria. FliA-dependent transcription of sdiA is required for transcriptional control of SdiA target genes, highlighting a regulatory link between flagellar motility and intercellular communication.

An Ensemble Method to Reconstruct Gene Regulatory Networks Based on Multivariate Adaptive Regression Splines.

Gene regulatory networks (GRNs) play a key role in biological processes. However, GRNs are diverse under different biological conditions. Reconstructing gene regulatory networks (GRNs) from gene expression has become an important opportunity and challenge in the past decades. Although there are a lot of existing methods to infer the topology of GRNs, such as mutual information, random forest, and partial least squares, the accuracy is still low due to the noise and high dimension of the expression data. In this paper, we introduce an ensemble Multivariate Adaptive Regression Splines (MARS) based method to reconstruct the directed GRNs from multifactorial gene expression data, called PBMarsNet. PBMarsNet incorporates part mutual information (PMI) to pre-weight the candidate regulatory genes and then uses MARS to detect the nonlinear regulatory links. Moreover, we apply bootstrap to run the MARS multiple times and average the outputs of each MARS as the final score of regulatory links. The results on DREAM4 challenge and DREAM5 challenge datasets show PBMarsNet has a superior performance and generalization over other state-of-the-art methods.

Influence of bacterial lectin on key regulatory links of functional activity of macrophages in mice with Ehrlich carcinoma.

Recent studies have shown the potential of using different approaches for immunotherapy in cancer treatment. Macrophages (Mph) are one of the promising targets for immunotherapy. To investigate changes in the functional activity of Mph in mice with Ehrlich carcinoma by nitric oxide (NO)/arginase (Arg), IRF4/IRF5and STAT1/STAT6ratios caused by administration of lectin from B. subtilis IMV-7724. From the 2nd day after Ehrlich carcinoma inoculation into female Balb/c mice, lectin from B. subtilis IMV B-7724 (0.02mg/mouse) was administered for 10days. The peritoneal Mph were isolated on days 14, 21, and 28after tumor transplantation and their functional state (NO production, Arg activity and cytotoxic activity) was examined. The levels of mRNA expression of transcription factors STAT-1, STAT-6, IRF5, IRF4were evaluated. In lectin-treated animals with Ehrlich carcinoma, the functional state of Mph (NO/Arg ratio, index of cytotoxic activity) was maintained at the level of intact mice exceeding the values in untreated animals with Ehrlich carcinoma at late terms of tumor growth (21, 28days). Analysis of mRNA expression levels of transcription factors in these animals showed a significant increase (p< 0.05) in the ratio of STAT1/STAT6on the day 21 and IRF5/IRF4on day 28 of tumor growth compared to that in untreated mice. Administration of lectin from B. subtilis IMV B-7724to mice with Ehrlich carcinoma led to the prevalence of Mph exhibiting the functional properties of M1type at late-term tumor growth. The transcription factors of the STAT and IRF signaling pathways are involved in the process of Mph polarization induced by lectin from B. subtilis IMV B-7724.

The features of delineation and division of areas of various functional types in the context of the state regional development strategy

The article considers issues related to modern approaches to delineation and division of territories on the basis of different functional types and studies of the implementation of these approaches provided by the State Strategy for Regional Development for 2021-2027. The purpose of the article is to analyze the peculiarities of the delineation and division of territories of different functional types in the context of the state strategy of regional development. Classical approaches to territorial development based on spatial development have led to long-term population decline at the regional and local levels, increasing socio-economic disparities and polarization of economic space, degradation of territorial entities, lack of proper infrastructure, and environmental degradation. The elaboration of regional development strategies has been strengthened by new methodological tools, which provide for the emergence of regulatory links with documents on spatial planning, taking into account environmental and spatial aspects, redistribution of investment in growth centers. The article determines that the use of a systematic approach to the allocation of functional territories according to various criteria in the State Strategy for Regional Development for 2021-2027 has provided the separation of the functional types of territorial entities the state regional policy will be based on. Legislative provisions of the State Strategy for Regional Development provide for a territorially oriented state regional policy, significantly influencing territorial development and increasing the competitiveness of regions. The article emphasizes that the modern state regional policy should move in the direction of a differentiated management approach to the types of functional territories defined by the current strategic document and the achievement of high quality of life in Ukraine.

Mud Loss Restricts Yki-Dependent Hyperplasia in Drosophila Epithelia.

Tissue development demands precise control of cell proliferation and organization, which is achieved through multiple conserved signaling pathways and protein complexes in multicellular animals. Epithelia are a ubiquitous tissue type that provide diverse functions including physical protection, barrier formation, chemical exchange, and secretory activity. However, epithelial cells are also a common driver of tumorigenesis; thus, understanding the molecular mechanisms that control their growth dynamics is important in understanding not only developmental mechanisms but also disease. One prominent pathway that regulates epithelial growth is the conserved Hippo/Warts/Yorkie network. Hippo/Warts inactivation, or activating mutations in Yorkie that prevent its phosphorylation (e.g., YkiS168A), drive hyperplastic tissue growth. We recently reported that loss of Mushroom body defect (Mud), a microtubule-associated protein that contributes to mitotic spindle function, restricts YkiS168A-mediated growth in Drosophila imaginal wing disc epithelia. Here we show that Mud loss alters cell cycle progression and triggers apoptosis with accompanying Jun kinase (JNK) activation in YkiS168A-expressing discs. To identify additional molecular insights, we performed RNAseq and differential gene expression profiling. This analysis revealed that Mud knockdown in YkiS168A-expressing discs resulted in a significant downregulation in expression of core basement membrane (BM) and extracellular matrix (ECM) genes, including the type IV collagen gene viking. Furthermore, we found that YkiS168A-expressing discs accumulated increased collagen protein, which was reduced following Mud knockdown. Our results suggest that ECM/BM remodeling can limit untoward growth initiated by an important driver of tumor growth and highlight a potential regulatory link with cytoskeleton-associated genes.

Analysis of Pan-omics Data in Human Interactome Network (APODHIN).

Analysis of Pan-omics Data in Human Interactome Network (APODHIN) is a platform for integrative analysis of transcriptomics, proteomics, genomics, and metabolomics data for identification of key molecular players and their interconnections exemplified in cancer scenario. APODHIN works on a meta-interactome network consisting of human protein–protein interactions (PPIs), miRNA-target gene regulatory interactions, and transcription factor-target gene regulatory relationships. In its first module, APODHIN maps proteins/genes/miRNAs from different omics data in its meta-interactome network and extracts the network of biomolecules that are differentially altered in the given scenario. Using this context specific, filtered interaction network, APODHIN identifies topologically important nodes (TINs) implementing graph theory based network topology analysis and further justifies their role via pathway and disease marker mapping. These TINs could be used as prospective diagnostic and/or prognostic biomarkers and/or potential therapeutic targets. In its second module, APODHIN attempts to identify cross pathway regulatory and PPI links connecting signaling proteins, transcription factors (TFs), and miRNAs to metabolic enzymes via utilization of single-omics and/or pan-omics data and implementation of mathematical modeling. Interconnections between regulatory components such as signaling proteins/TFs/miRNAs and metabolic pathways need to be elucidated more elaborately in order to understand the role of oncogene and tumor suppressors in regulation of metabolic reprogramming during cancer. APODHIN platform contains a web server component where users can upload single/multi omics data to identify TINs and cross-pathway links. Tabular, graphical and 3D network representations of the identified TINs and cross-pathway links are provided for better appreciation. Additionally, this platform also provides few example data analysis of cancer specific, single and/or multi omics dataset for cervical, ovarian, and breast cancers where meta-interactome networks, TINs, and cross-pathway links are provided. APODHIN platform is freely available at http://www.hpppi.iicb.res.in/APODHIN/home.html.