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We explored the dysregulation of G-protein-coupled receptor (GPCR) ligand systems in cancer transcriptomics datasets to uncover new therapeutics opportunities in oncology. We derived an interaction network of receptors with ligands and their biosynthetic enzymes. Multiple GPCRs are differentially regulated together with their upstream partners across cancer subtypes and are associated to specific transcriptional programs and to patient survival patterns. The expression of both receptor-ligand (or enzymes) partners improved patient stratification, suggesting a synergistic role for the activation of GPCR networks in modulating cancer phenotypes. Remarkably, we identified many such axes across several cancer molecular subtypes, including many involving receptor-biosynthetic enzymes for neurotransmitters. We found that GPCRs from these actionable axes, including, e.g., muscarinic, adenosine, 5-hydroxytryptamine, and chemokine receptors, are the targets of multiple drugs displaying anti-growth effects in large-scale, cancer cell drug screens, which we further validated. We have made the results generated in this study freely available through a webapp (gpcrcanceraxes.bioinfolab.sns.it).

AbstractIn chronic lymphocytic leukemia (CLL), TP53 mutations or deletions on chromosome 17p lead to adverse prognosis and reduced levels of miR-34a, which targets NOTCH1. Also, hyperactivated NOTCH1 signaling is crucial for CLL progression. Here we explored the interaction between p53, miR-34a, and NOTCH1 in CLL. We investigated the effect of p53 and miR-34a on NOTCH1 signaling and expression in CLL cells with altered TP53. Our results indicate that miR-34a reduces NOTCH1 3’ UTR activity but might not be a mediator between p53 signaling and NOTCH1. p53 activation increases miR-34a expression and NOTCH1 protein levels, correlating with decreased NOTCH1 and miR-34a levels in primary CLL cells with TP53 alterations. Some samples with high NOTCH1 levels presented increased BCL-2, suggesting an anti-apoptotic mechanism of a potentially direct p53-NOTCH1 relation in CLL. This study deepens the understanding of the p53-miR-34a-NOTCH1 signaling network, providing insights that could guide future therapeutic strategies for CLL. [ABSTRACT FROM AUTHOR]

The manuscript analyzes potential pre-mRNA biomarkers of Myasthenia gravis (MG) in thymoma in silico. GSE11967 data set and platform5188 from the Gene Expression Omnibus database apply for data preprocessing, normalization, and quality control. Quality metrics indicated high overall data integrity, with no significant outliers or batch effects detected. Differential expression analysis (DEG.) uses the limma package in R. We compared thymoma samples to normal thymus tissue to identify DEGs. The significance criteria are adjusted p -value <0.05 and a |log2 fold change| > 1. Functional enrichment and pathway analysis, ontology analysis, and KEGG pathway analysis further investigate the potential underlying biological processes. Despite the extensive use of gene expression profiling for identifying potential biomarkers and therapeutic targets, this study identifies DEGs ENSG00000112345 and ENSG00000234567 and pathways like hsa04110, hsa03013 and hsa04115 in thymoma with MG compared to normal thymus tissue using the GSE11967 dataset Plots like UMAP, Boxplot, Expression density and Mean variance demonstrate differential expression in disease and control group. The GSE11967 data set shows the presence of significant DEG and pathways in thymoma-associated MG tissue, compared to healthy tissue. A broader and integrative approach is needed to understand the complex expression biomarkers in thymoma in MG patients and other regulatory mechanisms that may contribute to the disease by multi-omic approaches. [ABSTRACT FROM AUTHOR]

This document explores the concept of self-organizing and excitable signaling networks in cell biology. It discusses how certain signaling networks exhibit spontaneous organization into dynamic spatial patterns and the role of excitability in cellular processes such as cell migration, mitosis, embryonic development, and immune activation. The authors emphasize the importance of understanding these networks in both individual cells and cell populations. The document also references related research papers on topics such as ERK activation, collective cell migration, and actin dynamics. [Extracted from the article]

Members of the calcium-dependent protein kinase (CDPK/CPK) and SNF-related protein kinase (SnRK) superfamilies are commonly found in plants and some protists. Our knowledge of client specificity of the members of this superfamily is fragmentary. As this family is represented by over 30 members in Arabidopsis thaliana, the identification of kinase-specific and overlapping client relationships is crucial to our understanding the nuances of this large family of kinases as directed towards signal transduction pathways. Herein, we used the kinase client (KiC) assay—a relative, quantitative, high-throughput mass spectrometry-based in vitro phosphorylation assay—to identify and characterize potential CPK/SnRK targets of Arabidopsis. Eight CPKs (1, 3, 6, 8, 17, 24, 28, and 32), four SnRKs (subclass 1 and 2), and PPCK1 and PPCK2 were screened against a synthetic peptide library that contains 2095 peptides and 2661 known phosphorylation sites. A total of 625 in vitro phosphorylation sites corresponding to 203 non-redundant proteins were identified. The most promiscuous kinase, CPK17, had 105 candidate target proteins, many of which had already been discovered. Sequence analysis of the identified phosphopeptides revealed four motifs: LxRxxS, RxxSxxR, RxxS, and LxxxxS, that were significantly enriched among CPK/SnRK clients. The results provide insight into both CPK- and SnRK-specific and overlapping signaling network architectures and recapitulate many known in vivo relationships validating this large-scale approach towards discovering kinase targets. [ABSTRACT FROM AUTHOR]

Neuroblastoma is the most common solid extracranial tumor during childhood; it displays extraordinary heterogeneous clinical courses, from spontaneous regression to poor outcome in high-risk patients due to aggressive growth, metastasizing, and treatment resistance. Therefore, the identification and detailed analysis of promising tumorigenic molecular mechanisms are inevitable. This review highlights the abnormal regulation of NF-κB, Nrf2, and Phox2B as well as their interactions among each other in neuroblastoma. NF-κB and Nrf2 play a key role in antioxidant responses, anti-inflammatory regulation and tumor chemoresistance. Recent studies revealed a regulation of NF-κB by means of the Nrf2/antioxidant response element (ARE) system. On the other hand, Phox2B contributes to the differentiation of immature sympathetic nervous system stem cells: this transcription factor regulates the expression of RET, thereby facilitating cell survival and proliferation. As observed in other tumors, we presume striking interactions between NF-κB, Nrf2, and Phox2B, which might constitute an important crosstalk triangle, whose decompensation may trigger a more aggressive phenotype. Consequently, these transcription factors could be a promising target for novel therapeutic approaches and hence, further investigation on their regulation in neuroblastoma shall be reinforced.

Calcium-dependent protein kinase (CDPK) is member of one of the most important signalling cascades operating inside the plant system due to its peculiar role as thermo-sensor. Here, we identified 28 full length putative CDPKs from wheat designated as TaCDPK (1-28). Based on digital gene expression, we cloned full length TaCPK-1 gene of 1691 nucleotides with open reading frame (ORF) of 548 amino acids (accession number OP125853). The expression of TaCPK-1 was observed maximum (3.1-fold) in leaf of wheat cv. HD2985 (thermotolerant) under T2 (38 ± 3 °C, 2 h), as compared to control. A positive correlation was observed between the expression of TaCPK-1 and other stress-associated genes (MAPK6, CDPK4, HSFA6e, HSF3, HSP17, HSP70, SOD and CAT) involved in thermotolerance. Global protein kinase assay showed maximum activity in leaves, as compared to root, stem and spike under heat stress. Immunoblot analysis showed abundance of CDPK protein in wheat cv. HD2985 (thermotolerant) in response to T2 (38 ± 3 °C, 2 h), as compared to HD2329 (thermosusceptible). Calcium ion (Ca2+), being inducer of CDPK, showed strong Ca-signature in the leaf tissue (Ca—622 ppm) of thermotolerant wheat cv. under heat stress, whereas it was minimum (Ca—201 ppm) in spike tissue. We observed significant variations in the ionome of wheat under HS. To conclude, TaCPK-1 plays important role in triggering signaling network and in modulation of HS-tolerance in wheat. [ABSTRACT FROM AUTHOR]

Core protein components of the abscisic acid (ABA) signaling network, pyrabactin resistance (PYR), protein phosphatases 2C (PP2C), and SNF1-related protein kinase 2 (SnRK2) are involved in the regulation of stomatal closure and gene expression downstream responses in Arabidopsis thaliana. Phosphatidic acid (PA) produced by the phospholipases Dα1 and Dδ (PLDs) in the plasma membrane has been identified as a necessary molecule in ABA-inducible stomatal closure. On the other hand, the involvement of PA in ABA-inducible gene expression has been suggested but remains a question. In this study, the involvement of PA in the ABA-inducible gene expression was examined in the model plant Arabidopsis thaliana and the canonical RD29A ABA-inducible gene that possesses a single ABA--responsive element (ABRE) in the promoter. The promoter activity and accumulation of the RD29A mRNA during ABA exposure to the plants were analyzed under conditions in which the production of PA by PLDs is abrogated through chemical and genetic modification. Changes in the subcellular localization of PA during the signal transduction were analyzed with confocal microscopy. The results obtained in this study suggest that inhibition of PA production by the PLDs does not affect the promoter activity of RD29A. PA produced by the PLDs and exogenously added PA in the plasma membrane are effectively incorporated into internal membranes to transduce the signal. However, exogenously added PA induces stomatal closure but not RD29A expression. This is because PA produced by the PLDs most likely inhibits the activity of not all but only the selected PP2C family members, the negative regulators of the RD29A promoter. This finding underscores the necessity for experimental verifications to adapt previous knowledge into a signaling network model before its construction. [ABSTRACT FROM AUTHOR]

Blood cells in Drosophila serve primarily innate immune responses. Various stressors influence blood cell homeostasis regarding both numbers and the proportion of blood cell types. The principle molecular mechanisms governing hematopoiesis are conserved amongst species and involve major signaling pathways like Notch, Toll, JNK, JAK/Stat or RTK. Albeit signaling pathways generally rely on the activity of protein kinases, their specific contribution to hematopoiesis remains understudied. Here, we assess the role of Serine/Threonine kinases with the potential to phosphorylate the transcription factor Su(H) in crystal cell homeostasis. Su(H) is central to Notch signal transduction, and its inhibition by phosphorylation impedes crystal cell formation. Overall, nearly twenty percent of all Drosophila Serine/Threonine kinases were studied in two assays, global and hemocyte-specific overexpression and downregulation, respectively. Unexpectedly, the majority of kinases influenced crystal cell numbers, albeit only a few were related to hematopoiesis so far. Four kinases appeared essential for crystal cell formation, whereas most kinases restrained crystal cell development. This group comprises all kinase classes, indicative of the complex regulatory network underlying blood cell homeostasis. The rather indiscriminative response we observed opens the possibility that blood cells measure their overall phospho-status as a proxy for stress-signals, and activate an adaptive immune response accordingly. [ABSTRACT FROM AUTHOR]

Culturing of mouse and human embryonic stem cells (ESCs) in vitro was a major breakthrough in the field of stem cell biology. These models gained popularity very soon mainly due to their pluripotency. Evidently, the ESCs of mouse and human origin share typical phenotypic responses due to their pluripotent nature, such as self-renewal capacity and potency. The conserved network of core transcription factors regulates these responses. However, significantly different signaling pathways and upstream transcriptional networks regulate expression and activity of these core pluripotency factors in ESCs of both the species. In fact, ample evidence shows that a pathway, which maintains pluripotency in mouse ESCs, promotes differentiation in human ESCs. In this review, we discuss the role of canonical signaling pathways implicated in regulation of pluripotency and differentiation particularly in mouse and human ESCs. We believe that understanding these distinct and at times—opposite mechanisms—is critical for the progress in the field of stem cell biology and regenerative medicine. [ABSTRACT FROM AUTHOR]

The Integrated Stress Response (ISR) is an essential homeostatic signaling network that controls the cell’s biosynthetic capacity. Four ISR sensor kinases detect multiple stressors and relay this information to downstream effectors by phosphorylating a common node: the alpha subunit of the eukaryotic initiation factor eIF2. As a result, general protein synthesis is repressed while select transcripts are preferentially translated, thus remodeling the proteome and transcriptome. Mounting evidence supports a view of the ISR as a dynamic signaling network with multiple modulators and feedback regulatory features that vary across cell and tissue types. Here, we discuss updated views on ISR sensor kinase mechanisms, how the subcellular localization of ISR components impacts signaling, and highlight ISR signaling differences across cells and tissues. Finally, we consider crosstalk between the ISR and other signaling pathways as a determinant of cell health. [ABSTRACT FROM AUTHOR]

Low back pain (LBP) is a worldwide problem with public health. Paravertebral muscle degeneration (PMD) is believed to be associated with LBP. Increasing evidence has demonstrated that microRNA (miRNA)-mRNA signaling networks have been implicated in the pathophysiology of diseases. Research suggests that cell death, oxidative stress, inflammatory and immune response, and extracellular matrix (ECM) metabolism are the pathogenesis of PMD; however, the miRNA-mRNA mediated the pathological process of PMD remains elusive. RNA sequencing (RNA-seq) and single cell RNA-seq (scRNA-seq) are invaluable tools for uncovering the functional biology underlying these miRNA and gene expression changes. Using scRNA-seq, we show that multiple immunocytes are presented during PMD, revealing that they may have been implicated with PMD. Additionally, using RNA-seq, we identified 76 differentially expressed genes (DEGs) and 106 differentially expressed miRNAs (DEMs), among which IL-24 and CCDC63 were the top upregulated and downregulated genes in PMD. Comprehensive bioinformatics analyses, including Venn diagrams, differential expression, functional enrichment, and protein-protein interaction analysis, were then conducted to identify six ferroptosis-related DEGs, two oxidative stress-related DEGs, eleven immunity-related DEGs, five ECM-related DEGs, among which AKR1C2/AKR1C3/SIRT1/ALB/IL-24 belong to inflammatory genes. Furthermore, 67 DEMs were predicted to be upstream miRNAs of 25 key DEGs by merging RNA-seq, TargetScan, and mirDIP databases. Finally, a miRNA-gene network was constructed using Cytoscape software and an alluvial plot. ROC curve analysis unveiled multiple key DEGs with the high clinical diagnostic value, providing novel approaches for diagnosing and treating PMD diseases.

Core protein components of the abscisic acid (ABA) signaling network, pyrabactin resistance (PYR), protein phosphatases 2C (PP2C), and SNF1-related protein kinase 2 (SnRK2) are involved in the regulation of stomatal closure and gene expression downstream responses in Arabidopsis thaliana. Phosphatidic acid (PA) produced by the phospholipases Dα1 and Dδ (PLDs) in the plasma membrane has been identified as a necessary molecule in ABA-inducible stomatal closure. On the other hand, the involvement of PA in ABA-inducible gene expression has been suggested but remains a question. In this study, the involvement of PA in the ABA-inducible gene expression was examined in the model plant Arabidopsis thaliana and the canonical RD29A ABA-inducible gene that possesses a single ABA–responsive element (ABRE) in the promoter. The promoter activity and accumulation of the RD29A mRNA during ABA exposure to the plants were analyzed under conditions in which the production of PA by PLDs is abrogated through chemical and genetic modification. Changes in the subcellular localization of PA during the signal transduction were analyzed with confocal microscopy. The results obtained in this study suggest that inhibition of PA production by the PLDs does not affect the promoter activity of RD29A. PA produced by the PLDs and exogenously added PA in the plasma membrane are effectively incorporated into internal membranes to transduce the signal. However, exogenously added PA induces stomatal closure but not RD29A expression. This is because PA produced by the PLDs most likely inhibits the activity of not all but only the selected PP2C family members, the negative regulators of the RD29A promoter. This finding underscores the necessity for experimental verifications to adapt previous knowledge into a signaling network model before its construction.

IntroductionPro-thrombotic events are one of the prevalent causes of intensive care unit (ICU) admissions among COVID-19 patients, although the signaling events in the stimulated platelets are still unclear.MethodsWe conducted a comparative analysis of platelet transcriptome data from healthy donors, ICU, and non-ICU COVID-19 patients to elucidate these mechanisms. To surpass previous analyses, we constructed models of involved networks and control cascades by integrating a global human signaling network with transcriptome data. We investigated the control of platelet hyperactivation and the specific proteins involved.ResultsOur study revealed that control of the platelet network in ICU patients is significantly higher than in non-ICU patients. Non-ICU patients require control over fewer proteins for managing platelet hyperactivity compared to ICU patients. Identification of indispensable proteins highlighted key subnetworks, that are targetable for system control in COVID-19-related platelet hyperactivity. We scrutinized FDA-approved drugs targeting indispensable proteins and identified fostamatinib as a potent candidate for preventing thrombosis in COVID-19 patients.DiscussionOur findings shed light on how SARS-CoV-2 efficiently affects host platelets by targeting indispensable and critical proteins involved in the control of platelet activity. We evaluated several drugs for specific control of platelet hyperactivity in ICU patients suffering from platelet hyperactivation. The focus of our approach is repurposing existing drugs for optimal control over the signaling network responsible for platelet hyperactivity in COVID-19 patients. Our study offers specific pharmacological recommendations, with drug prioritization tailored to the distinct network states observed in each patient condition. Interactive networks and detailed results can be accessed at https://fostamatinib.bioinfo-wuerz.eu/.

The Integrated Stress Response (ISR) is an essential homeostatic signaling network that controls the cell’s biosynthetic capacity. Four ISR sensor kinases detect multiple stressors and relay this information to downstream effectors by phosphorylating a common node: the alpha subunit of the eukaryotic initiation factor eIF2. As a result, general protein synthesis is repressed while select transcripts are preferentially translated, thus remodeling the proteome and transcriptome. Mounting evidence supports a view of the ISR as a dynamic signaling network with multiple modulators and feedback regulatory features that vary across cell and tissue types. Here, we discuss updated views on ISR sensor kinase mechanisms, how the subcellular localization of ISR components impacts signaling, and highlight ISR signaling differences across cells and tissues. Finally, we consider crosstalk between the ISR and other signaling pathways as a determinant of cell health.

Glial cell line-derived neurotrophic factor (GDNF) signals through a multi-component receptor system predominantly consisting of glycosyl-phosphatidylinositol-anchored GDNF family receptor alpha-1 (GFRα1) and the Rearranged during transfection (RET) receptor tyrosine kinase. GDNF/RET signaling is vital to the central and peripheral nervous system, kidney morphogenesis, and spermatogenesis. In addition, the dysregulation of the GDNF/RET signaling has been implicated in the pathogenesis of cancers. Despite the extensive research on GDNF/RET signaling, a molecular network of reactions induced by GDNF reported across the published literature. However, a comprehensive GDNF/RET pathway resource is currently unavailable. We describe an integrated signaling pathway reaction map of GDNF/RET consisting of 1151 molecular reactions. These include information pertaining to 52 molecular association events, 70 enzyme catalysis events, 36 activation/inhibition events, 22 translocation events, 856 gene regulation events, and 115 protein-level expression events induced by GDNF in diverse cell types. We developed a comprehensive GDNF/RET signaling network map based on these molecular reactions. The pathway map was made accessible through WikiPathways database (https://www.wikipathways.org/index.php/Pathway:WP5143). Biocuration and development of gene regulatory network map of GDNF/RET signaling pathway [ABSTRACT FROM AUTHOR]

Cytoskeleton-associated protein 4 (CKAP4) is a non-glycosylated type II transmembrane protein that serves as a cell surface-activated receptor. It is expressed primarily in the plasma membranes of bladder epithelial cells, type II alveolar pneumocytes, and vascular smooth muscle cells. CKAP4 is involved in various biological activities including cell proliferation, cell migration, keratinocyte differentiation, glycogenesis, fibrosis, thymic development, cardiogenesis, neuronal apoptosis, and cancer. CKAP4 has been described as a pro-tumor molecule that regulates the progression of various cancers, including lung cancer, breast cancer, esophageal squamous cell carcinoma, hepatocellular carcinoma, cervical cancer, oral cancer, bladder cancer, cholangiocarcinoma, pancreatic cancer, myeloma, renal cell carcinoma, melanoma, squamous cell carcinoma, colorectal cancer, and osteosarcoma. CKAP4 and its isoform bind to DKK1 or DKK3 (Dickkopf proteins) or antiproliferative factor (APF) and regulates several downstream signaling cascades. The CKAP4 complex plays a crucial role in regulating the signaling pathways including PI3K/AKT and MAPK1/3. Recently, CKAP4 has been recognized as a potential target for cancer therapy. Due to its biomedical importance, we integrated a network map of CKAP4. The available literature on CKAP4 signaling was manually curated according to the NetPath annotation criteria. The consolidated pathway map comprises 41 activation/inhibition events, 21 catalysis events, 35 molecular associations, 134 gene regulation events, 83 types of protein expression, and six protein translocation events. CKAP4 signaling pathway map data is freely accessible through the WikiPathways Database (https://www.wikipathways.org/index.php/Pathway:WP5322). Generation of CKAP4 signaling pathway map [ABSTRACT FROM AUTHOR]

Members of the calcium-dependent protein kinase (CDPK/CPK) and SNF-related protein kinase (SnRK) superfamilies are commonly found in plants and some protists. Our knowledge of client specificity of the members of this superfamily is fragmentary. As this family is represented by over 30 members in Arabidopsis thaliana, the identification of kinase-specific and overlapping client relationships is crucial to our understanding the nuances of this large family of kinases as directed towards signal transduction pathways. Herein, we used the kinase client (KiC) assay—a relative, quantitative, high-throughput mass spectrometry-based in vitro phosphorylation assay—to identify and characterize potential CPK/SnRK targets of Arabidopsis. Eight CPKs (1, 3, 6, 8, 17, 24, 28, and 32), four SnRKs (subclass 1 and 2), and PPCK1 and PPCK2 were screened against a synthetic peptide library that contains 2095 peptides and 2661 known phosphorylation sites. A total of 625 in vitro phosphorylation sites corresponding to 203 non-redundant proteins were identified. The most promiscuous kinase, CPK17, had 105 candidate target proteins, many of which had already been discovered. Sequence analysis of the identified phosphopeptides revealed four motifs: LxRxxS, RxxSxxR, RxxS, and LxxxxS, that were significantly enriched among CPK/SnRK clients. The results provide insight into both CPK- and SnRK-specific and overlapping signaling network architectures and recapitulate many known in vivo relationships validating this large-scale approach towards discovering kinase targets.

Aim: Disruption of the internal circadian rhythm pathway could lead to a range of diseases. In this study, we aim to evaluate the circadian rhythm pathway by assessing the interaction between CLOCK and CSNK1D genes in HTLV-1 carriers in comparison with healthy individuals. Materials & methods:CLOCK and CSNK1D gene expression was assessed using the RT-qPCR. Pathogenesis-related signaling networks were designed and analyzed using the obtained results. Results: There was no significant difference in age between the groups. CLOCK and CSNK1D gene expression levels were significantly higher in carriers than in healthy individuals (p = 0.04, p = 0.03, respectively). Conclusion: In addition to introducing potential biological markers, obtained results could be a good idea to further investigate this signaling pathway in the future. [ABSTRACT FROM AUTHOR]

In humans, more than 500 kinases phosphorylate ~15% of all proteins in an emerging phosphorylation network. Convergent local interaction motifs, in which ≥two kinases phosphorylate the same substrate, underlie feedback loops and signal amplification events but have not been systematically analyzed. Here, we first report a network‐wide computational analysis of convergent kinase‐substrate relationships (cKSRs). In experimentally validated phosphorylation sites, we find that cKSRs are common and involve >80% of all human kinases and >24% of all substrates. We show that cKSRs occur over a wide range of stoichiometries, in many instances harnessing co‐expressed kinases from family subgroups. We then experimentally demonstrate for the prototypical convergent CDK4/6 kinase pair how multiple inputs phosphorylate the tumor suppressor retinoblastoma protein (RB) and thereby hamper in situ analysis of the individual kinases. We hypothesize that overexpression of one kinase combined with a CDK4/6 inhibitor can dissect convergence. In breast cancer cells expressing high levels of CDK4, we confirm this hypothesis and develop a high‐throughput compatible assay that quantifies genetically modified CDK6 variants and inhibitors. Collectively, our work reveals the occurrence, topology, and experimental dissection of convergent interactions toward a deeper understanding of kinase networks and functions. [ABSTRACT FROM AUTHOR]

Background: Mass cytometry (CyTOF) gives unprecedented opportunity to simultaneously measure up to 40 proteins in single cells, with a theoretical potential to reach 100 proteins. This high-dimensional single-cell information can be very useful in dissecting mechanisms of cellular activity. In particular, measuring abundances of signaling proteins like phospho-proteins can provide detailed information on the dynamics of single-cell signaling processes. However, computational analysis is required to reconstruct such networks with a mechanistic model. Methods: We propose our Mass cytometry Signaling Network Analysis Code (McSNAC), a new software capable of reconstructing signaling networks and estimating their kinetic parameters from CyTOF data. McSNAC approximates signaling networks as a network of first-order reactions between proteins. This assumption often breaks down as signaling reactions can involve binding and unbinding, enzymatic reactions, and other nonlinear constructions. Furthermore, McSNAC may be limited to approximating indirect interactions between protein species, as cytometry experiments are only able to assay a small fraction of protein species involved in signaling. Results: We carry out a series of in silico experiments here to show (1) McSNAC is capable of accurately estimating the ground-truth model in a scalable manner when given data originating from a first-order system; (2) McSNAC is capable of qualitatively predicting outcomes to perturbations of species abundances in simple second-order reaction models and in a complex in silico nonlinear signaling network in which some proteins are unmeasured. Conclusions: These findings demonstrate that McSNAC can be a valuable screening tool for generating models of signaling networks from time-stamped CyTOF data. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) continues to be a lethal disease with no efficacious treatment modalities. The incidence of PDAC is expected to increase, at least partially because of the obesity epidemic. Increased efforts to prevent or intercept this disease are clearly needed. Mutations in KRAS are initiating events in pancreatic carcinogenesis supported by genetically engineered mouse models of the disease. However, oncogenic KRAS is not entirely sufficient for the development of fully invasive PDAC. Additional genetic mutations and/or environmental, nutritional, and metabolic stressors, e.g. inflammation and obesity, are required for efficient PDAC formation with activation of KRAS downstream effectors. Multiple factors "upstream" of KRAS associated with obesity, including insulin resistance, inflammation, changes in gut microbiota and GI peptides, can enhance/modulate downstream signals. Multiple signaling networks and feedback loops "downstream" of KRAS have been described that respond to obesogenic diets. We propose that KRAS mutations potentiate a signaling network that is promoted by environmental factors. Specifically, we envisage that KRAS mutations increase the intensity and duration of the growth-promoting signaling network. As the transcriptional activator YAP plays a critical role in the network, we conclude that the rationale for targeting the network (at different points), e.g. with FDA approved drugs such as statins and metformin, is therefore compelling.

Tubers and tuberous root crops are essential carbohydrate sources and staple foods for humans, second only to cereals. The developmental phase transition, including floral initiation and underground storage organ formation, is controlled by complex signaling processes involving the integration of environmental and endogenous cues. FLOWERING LOCUS T (FT) and TERMINAL FLOWER 1/CENTRORADIALIS (TFL1/CEN), members of the phosphatidylethanolamine-binding protein (PEBP) gene family, play a central role in this developmental phase transition process. FT and FT-like proteins have a function to promote developmental phase transition, while TFL1/CEN act oppositely. The balance between FT and TFL1/CEN is critical to ensure a successful plant life cycle. Here, we present a summarized review of the role and signaling network of PEBP in floral initiation and underground storage organ formation, specifically in tubers and tuberous root crops. Lastly, we point out several questions that need to be answered in order to have a more complete understanding of the PEBP signaling network, which is crucial for the agronomical improvement of tubers and tuberous crops. [ABSTRACT FROM AUTHOR]

Simple Summary: Reciprocal interactions between tumor and host cells in the tumor microenvironment critically influence the clinical outcome in ovarian carcinoma patients. Therefore, the identification of factors triggering central communication pathways controlling tumor growth and metastasis is highly relevant. This study was conducted to uncover the contribution of lipid mediators to this signaling network by different cell types in the tumor microenvironment and subsequent functional evaluation of clinically relevant candidates. We found that prostacyclin is mainly secreted by cancer-associated fibroblast and selectively acts on prostacyclin receptor-expressing macrophages to induce pro-tumorigenic and immunosuppressive features. Our findings improve the understanding of the tumor-promoting role of prostacyclin in ovarian carcinoma and identify prostacyclin synthesis in cancer-associated fibroblast as a potential target for improved treatment approaches. Metastasis of high-grade ovarian carcinoma (HGSC) is orchestrated by soluble mediators of the tumor microenvironment. Here, we have used transcriptomic profiling to identify lipid-mediated signaling pathways encompassing 41 ligand-synthesizing enzymes and 23 cognate receptors in tumor, immune and stroma cells from HGSC metastases and ascites. Due to its strong association with a poor clinical outcome, prostacyclin (PGI2) synthase (PTGIS) is of particular interest in this signaling network. PTGIS is highly expressed by cancer-associated fibroblasts (CAF), concomitant with elevated PGI2 synthesis, whereas tumor-associated macrophages (TAM) exhibit the highest expression of its surface receptor (PTGIR). PTGIR activation by PGI2 agonists triggered cAMP accumulation and induced a mixed-polarization macrophage phenotype with altered inflammatory gene expression, including CXCL10 and IL12A repression, as well as reduced phagocytic capability. Co-culture experiments provided further evidence for the interaction of CAF with macrophages via PGI2, as the effect of PGI2 agonists on phagocytosis was mitigated by cyclooxygenase inhibitors. Furthermore, conditioned medium from PGI2-agonist-treated TAM promoted tumor adhesion to mesothelial cells and migration in a PTGIR-dependent manner, and PTGIR activation induced the expression of metastasis-associated and pro-angiogenic genes. Taken together, our study identifies a PGI2/PTGIR-driven crosstalk between CAF, TAM and tumor cells, promoting immune suppression and a pro-metastatic environment. [ABSTRACT FROM AUTHOR]

Urotensin-II is a polypeptide ligand with neurohormone-like activity. It mediates downstream signaling pathways through G-protein-coupled receptor 14 (GPR14) also known as urotensin receptor (UTR). Urotensin-II is the most potent endogenous vasoconstrictor in mammals, promoting cardiovascular remodelling, cardiac fibrosis, and cardiomyocyte hypertrophy. It is also involved in other physiological and pathological activities, including neurosecretory effects, insulin resistance, atherosclerosis, kidney disease, and carcinogenic effects. Moreover, it is a notable player in the process of inflammatory injury, which leads to the development of inflammatory diseases. Urotensin-II/UTR expression stimulates the accumulation of monocytes and macrophages, which promote the adhesion molecules expression, chemokines activation and release of inflammatory cytokines at inflammatory injury sites. Therefore, urotensin-II turns out to be an important therapeutic target for the treatment options and management of associated diseases. The main downstream signaling pathways mediated through this urotensin-II /UTR system are RhoA/ROCK, MAPKs and PI3K/AKT. Due to the importance of urotensin-II systems in biomedicine, we consolidated a network map of urotensin-II /UTR signaling. The described signaling map comprises 33 activation/inhibition events, 31 catalysis events, 15 molecular associations, 40 gene regulation events, 60 types of protein expression, and 11 protein translocation events. The urotensin-II signaling pathway map is made freely accessible through the WikiPathways Database (https://www.wikipathways.org/index.php/Pathway:WP5158). The availability of comprehensive urotensin-II signaling in the public resource will help understand the regulation and function of this pathway in normal and pathological conditions. We believe this resource will provide a platform to the scientific community in facilitating the identification of novel therapeutic drug targets for diseases associated with urotensin-II signaling. [ABSTRACT FROM AUTHOR]

Combinations of multiple drugs are an important approach to maximize the chance for therapeutic success by inhibiting multiple pathways/targets. Analytic methods for studying drug combinations have received increasing attention because major advances in biomedical research have made available large number of potential agents for testing. The preclinical experiment on multi-drug combinations plays a key role in (especially cancer) drug development because of the complex nature of the disease, the need to reduce development time and costs. Despite recent progresses in statistical methods for assessing drug interaction, there is an acute lack of methods for designing experiments on multi-drug combinations. The number of combinations grows exponentially with the number of drugs and dose-levels and it quickly precludes laboratory testing. Utilizing experimental dose-response data of single drugs and a few combinations along with pathway/network information to obtain an estimate of the functional structure of the dose-response relationship in silico, we propose an optimal design that allows exploration of the dose-effect surface with the smallest possible sample size in this article. The simulation studies show our proposed methods perform well.

Background: Gallbladder Cancer (GBC) is one of the most common cancers of the biliary tract and the third commonest gastrointestinal (GI) malignancy worldwide. The disease is characterized by the late presentation and poor outcome despite treatment, and hence, newer therapies and targets need to be identified. Methods: The current study investigated various functionally enriched pathways in GBC pathogenesis involving the genes identified through Next Generation Sequencing (NGS) in a hospital-based cohort. The Pathway enrichment analysis and Gene Ontology (GO) were carried out after NGS, followed by the construction of the protein–protein interaction (PPI) network to discover associations among the genes. Results: Of the thirty-three patients with GBC who were screened through next-generation sequencing (NGS), 27somatic mutations were identified. These mutations involved a total of 14 genes. The p53 and KRAS were commonly found to be mutated, while mutations in other genes were seen in one case each, the mean number of mutations were 1.2, and maximum mutation in a single case (eight) was seen in one case. The bioinformatics analysis identified MAP kinase, PI3K-AKT, EGF/EGFR, and Focal Adhesion PI3K-AKT-mTOR signaling pathways and cross-talk between these. Conclusion: The results suggest that the complex crosstalk between the mTOR, MAPK, and multiple interacting cell signaling cascades can promote GBC progression, and hence, mTOR–MAPK targeted treatment will be an attractive option. [ABSTRACT FROM AUTHOR]

Objectives: Neuroinflammation signaling has been identified as an important hallmark of Alzheimer's disease (AD) in addition to amyloid b plaques (Ab) and neurofibrillary tangles (NFTs). However, the molecular mechanisms and biological processes of neuroinflammation remain unclear and have not well delineated using transcriptomics data available. Our objectives are to uncover the core neuroinflammation signaling pathways in AD using integrative network analysis on the transcriptomics data. Materials and methods: From a novel perspective, i.e., investigating weakly activated molecular signals (rather than the strongly activated molecular signals), we developed integrative and systems biology network analysis to uncover potential core neuroinflammation signaling targets and pathways in AD using the two large-scale transcriptomics datasets, i.e., Mayo Clinic (77 controls and 81 AD samples) and ROSMAP (97 controls and 260 AD samples). Results: Our analysis identified interesting core neuroinflammation signaling pathways, which are not systematically reported in the previous studies of AD. Specifically, we identified 7 categories of signaling pathways implicated on AD and related to virus infection: immune response, x-core signaling, apoptosis, lipid dysfunctional, biosynthesis and metabolism, and mineral absorption signaling pathways. More interestingly, most of the genes in the virus infection, immune response, and x-core signaling pathways are associated with inflammation molecular functions. The x-core signaling pathways were defined as a group of 9 signaling proteins: MAPK, Rap1, NFkappa B, HIF-1, PI3K-Akt, Wnt, TGF-beta, Hippo, and TNF, which indicated the core neuroinflammation signaling pathways responding to the low-level and weakly activated inflammation and hypoxia and leading to the chronic neurodegeneration. It is interesting to investigate the detailed signaling cascades of these weakly activated neuroinflammation signaling pathways causing neurodegeneration in a chronic process, and consequently uncover novel therapeutic targets for effective AD treatment and prevention. Conclusions: The potential core neuroinflammation and associated signaling targets and pathways were identified using integrative network analysis on two large-scale transcriptomics datasets of AD. [ABSTRACT FROM AUTHOR]

Bacteria find suitable locations for colonization by sensing and responding to surfaces. Complex signaling repertoires control surface colonization, and surface contact sensing by the flagellum plays a central role in activating colonization programs. Caulobacter crescentus adheres to surfaces using a polysaccharide adhesin called the holdfast. In C. crescentus , disruption of the flagellum through interactions with a surface or mutation of flagellar genes increases holdfast production. Our group previously identified several C. crescentus genes involved in flagellar surface sensing. One of these, fssF , codes for a protein with homology to the flagellar C-ring protein FliN. We show here that a fluorescently tagged FssF protein localizes to the flagellated pole of the cell and requires all components of the flagellar C-ring for proper localization, supporting the model that FssF associates with the C-ring. Deleting fssF results in a severe motility defect, which we show is due to a disruption of chemotaxis. Epistasis experiments demonstrate that fssF promotes adhesion through a stator-dependent pathway when late-stage flagellar mutants are disrupted. Separately, we find that disruption of chemotaxis through deletion of fssF or other chemotaxis genes results in a hyperadhesion phenotype. Key genes in the surface sensing network ( pleD , motB , and dgcB ) contribute to both ∆ flgH- dependent and ∆ fssF- dependent hyperadhesion, but these genes affect adhesion differently in the two hyperadhesive backgrounds. Our results support a model in which the stator subunits of the flagella incorporate both mechanical and chemical signals to regulate adhesion.IMPORTANCEBacterial biofilms pose a threat in clinical and industrial settings. Surface sensing is one of the first steps in biofilm formation. Studying surface sensing can improve our understanding of biofilm formation and develop preventative strategies. In this study, we use the freshwater bacterium Caulobacter crescentus to study surface sensing and the regulation of surface attachment. We characterize a previously unstudied gene, fssF , and find that it localizes to the cell pole in the presence of three proteins that make up a component of the flagellum called the C-ring. Additionally, we find that fssF is required for chemotaxis behavior but dispensable for swimming motility. Lastly, our results indicate that deletion of fssF and other genes required for chemotaxis results in a hyperadhesive phenotype. These results support that surface sensing requires chemotaxis for a robust response to a surface.

Cadmium (Cd) is a toxic heavy metal that poses a significant risk to both plant growth and human health. To mitigate or lessen Cd toxicity, plants have evolved a wide range of sensing and defense strategies. The gasotransmitter hydrogen sulfide (H 2 S) is involved in plant responses to Cd stress and exhibits a crucial role in modulating Cd tolerance through a well-orchestrated interaction with several signaling pathways. Here, we review potential experimental approaches to manipulate H 2 S signals, concluding that research on another gasotransmitter, namely nitric oxide (NO), serves as a good model for research on H 2 S. Additionally, we discuss potential strategies to leverage H 2 S-reguated Cd tolerance to improve plant performance under Cd stress., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Abstract Background StrongestPath is a Cytoscape 3 application that enables the analysis of interactions between two proteins or groups of proteins in a collection of protein–protein interaction (PPI) network or signaling network databases. When there are different levels of confidence over the interactions, the application is able to process them and identify the cascade of interactions with the highest total confidence score. Given a set of proteins, StrongestPath can extract a set of possible interactions between the input proteins, and expand the network by adding new proteins that have the most interactions with highest total confidence to the current network of proteins. The application can also identify any activating or inhibitory regulatory paths between two distinct sets of transcription factors and target genes. This application can be used on the built-in human and mouse PPI or signaling databases, or any user-provided database for some organism. Results Our results on 12 signaling pathways from the NetPath database demonstrate that the application can be used for indicating proteins which may play significant roles in a pathway by finding the strongest path(s) in the PPI or signaling network. Conclusion Easy access to multiple public large databases, generating output in a short time, addressing some key challenges in one platform, and providing a user-friendly graphical interface make StrongestPath an extremely useful application.

Abstract Molecular knowledge of biological processes is a cornerstone in omics data analysis. Applied to single‐cell data, such analyses provide mechanistic insights into individual cells and their interactions. However, knowledge of intercellular communication is scarce, scattered across resources, and not linked to intracellular processes. To address this gap, we combined over 100 resources covering interactions and roles of proteins in inter‐ and intracellular signaling, as well as transcriptional and post‐transcriptional regulation. We added protein complex information and annotations on function, localization, and role in diseases for each protein. The resource is available for human, and via homology translation for mouse and rat. The data are accessible via OmniPath’s web service ( https://omnipathdb.org/ ), a Cytoscape plug‐in, and packages in R/Bioconductor and Python, providing access options for computational and experimental scientists. We created workflows with tutorials to facilitate the analysis of cell–cell interactions and affected downstream intracellular signaling processes. OmniPath provides a single access point to knowledge spanning intra‐ and intercellular processes for data analysis, as we demonstrate in applications studying SARS‐CoV‐2 infection and ulcerative colitis.

Melanoma is one of the most common skin infections, has triggered significant morbidity and mortality across the globe. Previous studies have reported that mutations in CDKN2A signalling network is associated with cutaneous malignant melanoma. In the present study, initially, the BioGrid database was utilized, and then hierarchical clustering was performed to identify the CDKN2A signature pathways. In addition, a GO Enrichment analysis was investigated using DAVID (n=187 genes) toolkit. Subsequently, the cBioPortal cancer genomic platform was exploited using alteration ranked frequency to determine the role of the CDKN2A signaling network in 363 samples of cutaneous malignant melanoma patients and we find that CDKN2A and its close interactors PTEN and HUWE1 show highest mutations. Further, we systematically employed molecular docking approach via MOE to target PTEN, CDKN2A and HUWE1 with chloroquine which is naturally occurring in medicinal plant Nigella sativa (NS) and observed virtuous interactions between all receptors and ligand molecules with a binding energy of -11.379, -10.324 and -9.06 Kcal/mol, respectively. The outcomes obtained stipulate a vigorous research resource for using chloroquine as a multitargeted anticancer drug. This novel evidence should help the development of effective therapeutic compounds for the treatment of cancer. Our results reveal that chloroquine is a relevant and novel potential therapeutic drug for the treatment of melanoma. [ABSTRACT FROM AUTHOR]

A fundamental biological question is how diverse and complex signaling and patterning is controlled correctly to generate distinct tissues, organs, and body plans, but incorrectly in diseased cells and tissues. Signaling pathways important for growth control have been identified, but to identify the mechanisms their transient and context-dependent interactions encode is more difficult. Currently computational systems biology aims to infer the control mechanisms by investigating quantitative changes of gene expression and protein concentrations, but this inference is difficult in nature. We propose it is desirable to explicitly simulate events and orders of gene regulation and protein interactions, which better elucidate control mechanisms, and report a method and tool with three examples. The Drosophila wing model includes Wnt, PCP, and Hippo pathways and mechanical force, incorporates well-confirmed experimental findings, and generates novel results. The other two examples illustrate the building of three-dimensional and large-scale models. These examples support that reconstructed spatiotemporal distributions of key signaling events help elucidate growth control mechanisms. As biologists pay increasing attention to disordered signaling in diseased cells, to develop new modeling methods and tools for conducting new computational studies is important.

Aortic valve stenosis (AVS) patients experience pathogenic valve leaflet stiffening due to excessive extracellular matrix (ECM) remodeling. Numerous microenvironmental cues influence pathogenic expression of ECM remodeling genes in tissue-resident valvular myofibroblasts, and the regulation of complex myofibroblast signaling networks depends on patient-specific extracellular factors. Here, we combined a manually curated myofibroblast signaling network with a data-driven transcription factor network to predict patient-specific myofibroblast gene expression signatures and drug responses. Using transcriptomic data from myofibroblasts cultured with AVS patient sera, we produced a large-scale, logic-gated differential equation model in which 11 biochemical and biomechanical signals were transduced via a network of 334 signaling and transcription reactions to accurately predict the expression of 27 fibrosis-related genes. Correlations were found between personalized model-predicted gene expression and AVS patient echocardiography data, suggesting links between fibrosisrelated signaling and patient-specific AVS severity. Further, global network perturbation analyses revealed signaling molecules with the most influence over network-wide activity, including endothelin 1 (ET1), interleukin 6 (IL6), and transforming growth factor β (TGFβ), along with downstream mediators c-Jun N-terminal kinase (JNK), signal transducer and activator of transcription (STAT), and reactive oxygen species (ROS). Lastly, we performed virtual drug screening to identify patient-specific drug responses, which were experimentally validated via fibrotic gene expression measurements in valvular interstitial cells cultured with AVS patient sera and treated with or without bosentan—a clinically approved ET1 receptor inhibitor. In sum, our work advances the ability of computational approaches to provide a mechanistic basis for clinical decisions including patient stratification and personalized drug screening [ABSTRACT FROM AUTHOR]

Rapid development of molecular genetic technologies made it possible to analyze in detail the phenomena that can be attributed to epigenetics, i.e., phenotypic switches in bacterial cell cultures. Phenotypic changes against the background of an unchanged genome can be a temporary reaction to external factors and disappear with the change of conditions or can be caused by cell differentiation and maintained regardless of external factors. In the literature, extremely heterogeneous terminology with synonymous terms for these phenomena is used, depending on their characteristics (bistability, specialization, hysteresis, phase variation, dissociation). One of the objectives of this review is to systematize the terminology used. Representatives of the genus Bacillus were selected as an object of analysis, since they exhibit a considerable number of epigenetic phenomena. In addition, bistability is an important factor affecting the efficiency of using bacteria of the genus Bacillus in biotechnological processes. The study provides a brief overview of epigenetic switches in the genus Bacillus, their mechanisms, methods of detection and analysis, and possible evolutionary and ecological role, as well as practical applications. [ABSTRACT FROM AUTHOR]

Although comprehensive exertions have been made in late decades for treating advanced lung cancer with inclusive therapies but efficient anti‐lung cancer therapeutics are statically inadequate in the clinics. Hence, compelling novel anti‐lung cancer drugs are considerably desired. This backdrop enticed us to unveil anticancer efficacy of astrakurkurol, derivative of wild edible mushroom against lung cancer, whose effects have not yet been described. Mechanistic analysis disclosed that sensitizing effect of astrakurkurol is due to cell cycle arrest at G0/G1 phase, increased level of Fas, FADD, decreased ratio of Bax/Bcl‐2, and increased cleaved form of caspase 9, 8, and 3. Apart from the induction of apoptosis, it was demonstrated for the first time that astrakurkurol induced an autophagic response as evidenced by the development of acidic vesicular organelles (AVOs) with up‐regulation of beclin‐1, Atg7, and downregulated p62. Apoptosis and autophagy can be sparked by the same stimuli, which was as evident from the astrakurkurol‐induced inactivation of PI3K/AKT signaling. The thorough scanning of the mechanism of crosstalk between apoptosis and autophagy is requisite for prosperous anticancer remedy. Triterpenoid has evidently intensified cytotoxicity, induced apoptosis and autophagy on A549 cells. Besides astrakurkurol could also curb migration and regress the size of tumor in ex ovo xenograft model. All these findings put forth astrakurkurol as a convincing novel anti‐cancer agent, for scrutinizing the lung cancer therapies and as a robust contender for future in vitro and in vivo analysis. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) is a free-radical gasotransmitter signaling molecule associated with a varied spectrum of signal transduction pathways linked to inducing cross-adaptation against abiotic stresses. It has crucial roles from seed germination to plant maturity, depending upon its cellular concentration. The functional cross-talk of NO among different stress signaling cascades leads to alteration in the expression of developmental genes that regulate biosynthesis and function of plant growth regulators (PGRs). NO-PGRs and secondary signaling compounds cross-talk trigger reprogramming of stress-responsive gene expressions, transcriptional gene modulations, redox regulating machinery, oxidative metabolisms, and multiple regulatory pathways under plant abiotic stress. Recent findings suggest NO as critical components of numerous plant signaling network that interplays with auxin, gibberellins (GA), abscisic acid (ABA), ethylene (ET), jasmonic acid (JA), brassinosteroids (BRs), H2O2, melatonin, hydrogen sulfide (H2S), salicylic acid (SA), and other PGRs to modulate growth and development under multiple stresses. Considering the importance of NO signaling crosstalk under stress adaptation, in this review, we point out the biosynthesis and metabolism of NO and its crosstalk with numerous other signaling compounds. Further, recent cellular and molecular advances in NO signaling cross-talk under abiotic stress adaptations also have been discussed. [ABSTRACT FROM AUTHOR]

5G network architecture,network characteristics and network deployment requirements of 5G typical services were mainly described.At the same time,5G core network,5G bearer network,5G access network end-to-end networking scheme suggestions were put forward,and 5G signaling network organization and routing mode in multiple scenarios were proposed,in order to provide reference for speeding up the commercial deployment of 5G network for telecom operators.

Regional control of fibrosis after myocardial infarction is critical for maintaining structural integrity in the infarct while preventing collagen accumulation in non-infarcted areas. Cardiac fibroblasts modulate matrix turnover in response to biochemical and biomechanical cues, but the complex interactions between signaling pathways confound efforts to develop therapies for regional scar formation. We employed a logic-based ordinary differential equation model of fibroblast mechano-chemo signal transduction to predict matrix protein expression in response to canonical biochemical stimuli and mechanical tension. Functional analysis of mechano-chemo interactions showed extensive pathway crosstalk with tension amplifying, dampening, or reversing responses to biochemical stimuli. Comprehensive drug target screens identified 13 mechano-adaptive therapies that promote matrix accumulation in regions where it is needed and reduce matrix levels in regions where it is not needed. Our predictions suggest that mechano-chemo interactions likely mediate cell behavior across many tissues and demonstrate the utility of multi-pathway signaling networks in discovering therapies for context-specific disease states.

Tubers and tuberous root crops are essential carbohydrate sources and staple foods for humans, second only to cereals. The developmental phase transition, including floral initiation and underground storage organ formation, is controlled by complex signaling processes involving the integration of environmental and endogenous cues. FLOWERING LOCUS T (FT) and TERMINAL FLOWER 1/CENTRORADIALIS (TFL1/CEN), members of the phosphatidylethanolamine-binding protein (PEBP) gene family, play a central role in this developmental phase transition process. FT and FT-like proteins have a function to promote developmental phase transition, while TFL1/CEN act oppositely. The balance between FT and TFL1/CEN is critical to ensure a successful plant life cycle. Here, we present a summarized review of the role and signaling network of PEBP in floral initiation and underground storage organ formation, specifically in tubers and tuberous root crops. Lastly, we point out several questions that need to be answered in order to have a more complete understanding of the PEBP signaling network, which is crucial for the agronomical improvement of tubers and tuberous crops.

The analysis of drug-induced gene expression profiles (DIGEP) is widely used to estimate the potential therapeutic and adverse drug effects as well as the molecular mechanisms of drug action. However, the corresponding experimental data is absent for many existing drugs and drug-like compounds. To solve this problem, we created the DIGEP-Pred 2.0 web application, which allows predicting DIGEP and potential drug targets by structural formula of drug-like compounds. It is based on the combined use of structure-activity relationships (SARs) and network analysis. SAR models were created using PASS (Prediction of Activity Spectra for Substances) technology for data from the Comparative Toxicogenomics Database (CTD), the Connectivity Map (CMap) for the prediction of DIGEP, and PubChem and ChEMBL for the prediction of molecular mechanisms of action (MoA). Using only the structural formula of a compound, the user can obtain information on potential gene expression changes in several cell lines and drug targets, which are potential master regulators responsible for the observed DIGEP. The mean accuracy of prediction calculated by leave-one-out cross validation was 86.5 % for 13377 genes and 94.8 % for 2932 proteins (CTD data), and it was 97.9 % for 2170 MoAs. SAR models (mean accuracy-87.5 %) were also created for CMap data given on MCF7, PC3, and HL60 cell lines with different threshold values for the logarithm of fold changes: 0.5, 0.7, 1, 1.5, and 2. Additionally, the data on pathways (KEGG, Reactome), biological processes of Gene Ontology, and diseases (DisGeNet) enriched by the predicted genes, together with the estimation of target-master regulators based on OmniPath data, is also provided. DIGEP-Pred 2.0 web application is freely available at https://www.way2drug.com/digep-pred., (© 2024 Wiley-VCH GmbH.)