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Exercise-induced muscle adaptations vary based on exercise modality and intensity. We constructed a signalling network model from 87 published studies of human or rodent skeletal muscle cell responses to endurance or resistance exercise in vivo or simulated exercise in vitro. The network comprises 259 signalling interactions between 120 nodes, representing eight membrane receptors and eight canonical signalling pathways regulating 14 transcriptional regulators, 28 target genes and 12 exercise-induced phenotypes. Using this network, we formulated a logic-based ordinary differential equation model predicting time-dependent molecular and phenotypic alterations following acute endurance and resistance exercises. Compared with nine independent studies, the model accurately predicted 18/21 (85%) acute responses to resistance exercise and 12/16 (75%) acute responses to endurance exercise. Detailed sensitivity analysis of differential phenotypic responses to resistance and endurance training showed that, in the model, exercise regulates cell growth and protein synthesis primarily by signalling via mechanistic target of rapamycin, which is activated by Akt and inhibited in endurance exercise by AMP-activated protein kinase. Endurance exercise preferentially activates inflammation via reactive oxygen species and nuclear factor κB signalling. Furthermore, the expected preferential activation of mitochondrial biogenesis by endurance exercise was counterbalanced in the model by protein kinase C in response to resistance training. This model provides a new tool for investigating cross-talk between skeletal muscle signalling pathways activated by endurance and resistance exercise, and the mechanisms of interactions such as the interference effects of endurance training on resistance exercise outcomes.

ETHYLENE RESPONSE FACTOR6 (ERF6) has emerged as a central player in stress‐induced plant growth inhibition. It orchestrates complex pathways that enable plants to acclimate and thrive in challenging environments. In response to various abiotic and biotic stresses, ERF6 is promptly activated through both ethylene‐dependent and ‐independent pathways, and contributes to enhanced stress tolerance mechanisms by activating a broad spectrum of genes at various developmental stages. Despite the crucial role of ERF6, there is currently a lack of published comprehensive insights into its function in plant growth and stress response. In this respect, based on the tight connection between ethylene and ERF6, we review the latest research findings on how ethylene regulates stress responses and the mechanisms involved. In addition, we summarize the trends and advances in ERF6‐mediated plant performance under optimal and stressful conditions. Finally, we also highlight key questions and suggest potential paths to unravel the ERF6 regulon in future research. Summary statement: The ETHYLENE RESPONSE FACTOR 6 (ERF6) is a central regulator of plant growth and stress response in Arabidopsis thaliana. In this work, we review the recent advances in our common understanding of the role of ethylene in growth and stress responses, and the contribution of ERF6 therein. [ABSTRACT FROM AUTHOR]

Protein interaction databases are critical resources for network bioinformatics and integrating molecular experimental data. Interaction databases may also enable construction of predictive computational models of biological networks, although their fidelity for this purpose is not clear. Here, we benchmark protein interaction databases X2K, Reactome, Pathway Commons, Omnipath and Signor for their ability to recover manually curated edges from three logic‐based network models of cardiac hypertrophy, mechano‐signalling and fibrosis. Pathway Commons performed best at recovering interactions from manually reconstructed hypertrophy (137 of 193 interactions, 71%), mechano‐signalling (85 of 125 interactions, 68%) and fibroblast networks (98 of 142 interactions, 69%). While protein interaction databases successfully recovered central, well‐conserved pathways, they performed worse at recovering tissue‐specific and transcriptional regulation. This highlights a knowledge gap where manual curation is critical. Finally, we tested the ability of Signor and Pathway Commons to identify new edges that improve model predictions, revealing important roles of protein kinase C autophosphorylation and Ca2+/calmodulin‐dependent protein kinase II phosphorylation of CREB in cardiomyocyte hypertrophy. This study provides a platform for benchmarking protein interaction databases for their utility in network model construction, as well as providing new insights into cardiac hypertrophy signalling. Key points: Protein interaction databases are used to recover signalling interactions from previously developed network models.The five protein interaction databases benchmarked recovered well‐conserved pathways, but did poorly at recovering tissue‐specific pathways and transcriptional regulation, indicating the importance of manual curation.We identify new signalling interactions not previously used in the network models, including a role for Ca2+/calmodulin‐dependent protein kinase II phosphorylation of CREB in cardiomyocyte hypertrophy. [ABSTRACT FROM AUTHOR]

Abstract Exercise‐induced muscle adaptations vary based on exercise modality and intensity. We constructed a signalling network model from 87 published studies of human or rodent skeletal muscle cell responses to endurance or resistance exercise in vivo or simulated exercise in vitro. The network comprises 259 signalling interactions between 120 nodes, representing eight membrane receptors and eight canonical signalling pathways regulating 14 transcriptional regulators, 28 target genes and 12 exercise‐induced phenotypes. Using this network, we formulated a logic‐based ordinary differential equation model predicting time‐dependent molecular and phenotypic alterations following acute endurance and resistance exercises. Compared with nine independent studies, the model accurately predicted 18/21 (85%) acute responses to resistance exercise and 12/16 (75%) acute responses to endurance exercise. Detailed sensitivity analysis of differential phenotypic responses to resistance and endurance training showed that, in the model, exercise regulates cell growth and protein synthesis primarily by signalling via mechanistic target of rapamycin, which is activated by Akt and inhibited in endurance exercise by AMP‐activated protein kinase. Endurance exercise preferentially activates inflammation via reactive oxygen species and nuclear factor κB signalling. Furthermore, the expected preferential activation of mitochondrial biogenesis by endurance exercise was counterbalanced in the model by protein kinase C in response to resistance training. This model provides a new tool for investigating cross‐talk between skeletal muscle signalling pathways activated by endurance and resistance exercise, and the mechanisms of interactions such as the interference effects of endurance training on resistance exercise outcomes.

Although cholesterol is essential for cellular viability and proliferation, it is highly toxic in excess. The concentration of cellular cholesterol must therefore be maintained within tight tolerances, and is thought to be subject to a stringent form of homeostasis known as Robust Perfect Adaptation (RPA). While much is known about the cellular signalling interactions involved in cholesterol regulation, the specific chemical reaction network structures that might be responsible for the robust homeostatic regulation of cellular cholesterol have been entirely unclear until now. In particular, the molecular mechanisms responsible for sensing excess whole-cell cholesterol levels have not been identified previously, and no mathematical models to date have been able to capture an integral control implementation that could impose RPA on cellular cholesterol. Here we provide a detailed mathematical description of cholesterol regulation pathways in terms of biochemical reactions, based on an extensive review of experimental and clinical literature. We are able to decompose the associated chemical reaction network structures into several independent subnetworks, one of which is responsible for conferring RPA on several intracellular forms of cholesterol. Remarkably, our analysis reveals that RPA in the cholesterol concentration in the endoplasmic reticulum (ER) is almost certainly due to a well-characterised control strategy known as antithetic integral control which, in this case, involves the high-affinity binding of a multi-molecular transcription factor complex with cholesterol molecules that are excluded from the ER membrane. Our model provides a detailed framework for exploring the necessary biochemical conditions for robust homeostatic control of essential and tightly regulated cellular molecules such as cholesterol.

Global Climate change has adversely affected the production and productivity of agriculturally important crops. Wheat, being staple food grain crop, is highly sensitive to terminal heat stress. The mechanism of heat stress tolerance has yet not been elucidated in wheat. The tolerance against heat stress has been reported to be quantitative trait controlled by large number of genes/QTLs. Various studies have resulted in detection of about 500 QTLs for various traits associated with heat stress tolerance on all the 21 chromosomes, maximum on 3B. Plants have developed very diverse signal networks and out of all the signalling pathways known and characterized, Ca2+-secondary messenger linked pathways are very predominant in plants. Ca2+-binding proteins have been classified into calcium-dependent protein kinases (CDPKs), calmodulins and calcineurin B-like proteins. CDPK, being prominent member, showed the presence of N-terminal domain (which is variable), a protein kinase domain (shows phosphorylation activity), an auto-inhibitory region and a calmodulin-like domain with EF-hand Ca2+-binding sites. CDPKs have been characterized to play very important role in the regulation of guard cells and in ABA-regulated stomatal signalling in Arabidopsis. OsCDPK7 and OsCDPK13 present in rice have been reported to modulate the tolerance level against cold, salt and drought stresses. CDPKs have also been identified to protect plants against abiotic stresses through regulating oxidative damage or ROS homeostasis. The actual sensory and signalling molecules and/or the primary targets of CPKs mediated regulation of photosynthesis and carbon assimilation metabolism under the heat stress are still unclear. It is worthwhile to examine the role of CDPKs in altering the photosynthesis and source to sink carbon transfer in wheat under heat stress. [ABSTRACT FROM AUTHOR]

The target of rapamycin (TOR) signalling network plays a pivotal role in regulating sugar metabolism and life-span in yeast, plants and mammals, in which TOR functions as a crucial protein. In plants, the TOR complex comprises TOR, RAPTOR (regulatory-associated protein of TOR) and LST8 (lethal with SEC13 protein 8). Factors like light, auxin, glucose, sucrose and amino acid can activate TOR protein as upstream signals to further phosphorylate downstream factors of TOR which promote cell proliferation and growth in plants. In this review, we analyse the TOR signalling network in plants and discuss the relationship between glucose and TOR, as well as the dynamic balance between TOR and sucrose-non-fermenting-related protein kinases (SnRKs). Given that 63 novel TOR-regulated proteins have been identified in previous studies, we also believe there are many unknown functions of TOR that need to be further investigated. The hot issue is the TOR signalling network in plants. In the context of plants, we discuss the TOR complex, the TOR signalling network, glucose–TOR signalling, TOR-SnRKs signalling pathway as well as the unknown functions of TOR. Recent studies have revealed that TOR plays various functions in the development of plants, and there is work to be done to answer questions about TOR proteins in plants. [ABSTRACT FROM AUTHOR]

Ras GTPases convey signals from different types of membranes. At these locations, different Ras isoforms, interactors and regulators generate different biochemical signals and biological outputs. The study of Ras localisation-specific signal transduction networks has been hampered by our inability to specifically activate each of these Ras pools. Here, we describe a new set of site-specific tethered exchange factors, engineered by fusing the RasGRF1 CDC25 domain to sub-localisation-defining cues, whereby Ras pools at specific locations can be precisely activated. We show that the CDC25 domain has a high specificity for activating HRas but not NRas and KRas. This unexpected finding means that our constructs mainly activate endogenous HRas. Hence, their use enabled us to identify distinct pathways regulated by HRas in endomembranes and plasma membrane microdomains. Importantly, these new constructs unveil different patterns of HRas activity specified by their subcellular localisation. Overall, the targeted GEFs described herein constitute ideal tools for dissecting spatially-defined HRas biochemical and biological functions. [ABSTRACT FROM AUTHOR]

Over the course of coevolution, plants have acquired a number of mechanisms to adaptively respond to a wide variety of microbes including pathogens and mutualists that affect plant fitness. Although widely recognized as a central regulator in plant adaptation to abiotic stresses as well as in plant growth and development, abscisic acid (ABA) also acts as a key modulator of plant responses to microbes. Effects of ABA on plant-pathogen interactions differ depending on the stages and modes of pathogen infection, but in many cases ABA negatively regulates plant immunity. This is reflected by the fact that some pathogens produce ABA on their own or induce ABA accumulation in the infected plants to promote infection. In mutualistic plant-microbe interactions, ABA generally promotes plant colonization by arbuscular mycorrhizal fungi but suppresses that by rhizobia. ABA interacts antagonistically or synergistically with multiple signaling components that regulate plant responses to pathogens and mutualists, including jasmonic acid, ethylene, salicylic acid, gibberellin, cytokinin and mitogen-activated protein kinases. This ABA signaling network likely enables plants to integrate ABA-regulated stress responses and developmental processes into their responses to pathogens and mutualists for optimizing plant fitness. In this chapter, I review the current understanding of ABA-mediated modulation of plant interactions with pathogenic and mutualistic microbes and illuminate the underlying mechanisms with a focus on crosstalk between ABA and other signaling components. [ABSTRACT FROM AUTHOR]

Abstract There is a lack of knowledge about the possibility that plants facing abiotic stressors, such as drought, have an altered perception of a pulse of O 3 and incur in alterations of their signalling network. This poses some concerns as to whether defensive strategy to cope episodic O 3 peaks in healthy plants may fail under stress. In this study, a set of saplings of two Mediterranean deciduous species, Quercus cerris and Q. pubescens , was subjected to water withholding (20% of daily evapotranspiration for 15 days) while another set was kept well-watered. Saplings were then subjected to a pulse of O 3 (200 nl l−1 for 5 h) or maintained in filtered air. Q. pubescens had a more severe decline of photosynthesis and leaf PDΨ w (about −65% and 5-fold lower than in well-watered ones) and events of cell death were observed under drought when compared to Q. cerris , which is supportive for a higher sensitivity to drought exhibited by this species. When O 3 was applied after drought, patterns of signalling compounds were altered in both species. Only in Q. pubescens , the typical O 3 -induced accumulation of apoplastic reactive oxygen species, which is the first necessary step for the activation of signalling cascade, was completely lost. In Q. cerris the most frequent changes encompassed the weakening of peaks of key signalling molecules (ethylene and salicylic acid), whereas in Q. pubescens both delayed (salicylic and jasmonic acid) or weakened (ethylene and salicylic acid) peaks were observed. This is translated to a higher ability of Q. cerris to maintain a prompt activation of defensive reaction to counteract oxidative damage due to the pollutant. Our results reveal the complexity of the signalling network in plants facing multiple stresses and highlight the need to further investigate possible alteration of defensive mechanism of tree species to predict their behavior. Graphical abstract Unlabelled Image Highlights • Possible alteration of O 3 -signalling wave by drought was investigated in oak species. • Two Mediterranean deciduous species with different water requirements were compared. • Gas exchange, chlorophyll a fluorescence and main signalling molecules were assessed. • Drought alters profoundly the typical O 3 -triggered reaction cascade. • Prediction of future plant behavior requires the deepening of signalling pattern. [ABSTRACT FROM AUTHOR]

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) is a crucial innate defence mechanism against viral infection in the innate immune system, as it principally induces the production of type I interferons. Immune responses and metabolic control are inextricably linked, and chronic low-grade inflammation promotes the development of metabolic diseases. The cGAS-STING pathway activated by double-stranded DNA (dsDNA), cyclic dinucleotides (CDNs), endoplasmic reticulum stress (ER stress), mitochondrial stress, and energy imbalance in metabolic cells and immune cells triggers proinflammatory responses and metabolic disorders. Abnormal overactivation of the pathway is closely associated with metabolic diseases such as obesity, nonalcoholic fatty liver disease (NAFLD), insulin resistance and cardiovascular diseases (CVDs). The interaction of cGAS-STING with other pathways, such as the nuclear factor-kappa B (NF-κB), Jun N-terminal kinase (JNK), AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), autophagy, pyroptosis and insulin signalling pathways, is considered an important mechanism by which cGAS-STING regulates inflammation and metabolism. This review focuses on the link between immune responses related to the cGAS-STING pathway and metabolic diseases and cGAS-STING interaction with other pathways for mediating signal input and affecting output. Moreover, potential inhibitors of the cGAS-STING pathway and therapeutic prospects against metabolic diseases are discussed. This review provides a comprehensive perspective on the involvement of STING in immune-related metabolic diseases., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

For a Boolean network we consider asynchronous updates and define the exclusive asynchronous basin of attraction for any steady state or cyclic attractor. An algorithm based on commutative algebra is presented to compute the exclusive basin. Finally its use for targeting desirable attractors by selective intervention on network nodes is illustrated with two examples, one cell signalling network and one sensor network measuring human mobility. [ABSTRACT FROM AUTHOR]

The MST/Hippo signalling pathway was first described over a decade ago in Drosophila melanogaster and the core of the pathway is evolutionary conserved in mammals. The mammalian MST/Hippo pathway regulates organ size, cell proliferation and cell death. In addition, it has been shown to play a central role in the regulation of cellular homeostasis and it is commonly deregulated in human tumours. The delineation of the canonical pathway resembles the behaviour of the Hippo pathway in the fly where the activation of the core kinases of the pathway prevents the proliferative signal mediated by the key effector of the pathway YAP. Nevertheless, several lines of evidence support the idea that the mammalian MST/Hippo pathway has acquired new features during evolution, including different regulators and effectors, crosstalk with other essential signalling pathways involved in cellular homeostasis and the ability to actively trigger cell death. Here we describe the current knowledge of the mechanisms that mediate MST/Hippo dependent cell death, especially apoptosis. We include evidence for the existence of complex signalling networks where the core proteins of the pathway play a central role in controlling the balance between survival and cell death. Finally, we discuss the possible involvement of these signalling networks in several human diseases such as cancer, diabetes and neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Micro RNAs (mi RNAs) are small non-coding RNAs that regulate translation of m RNA into protein and play a crucial role for almost all biological activities. However, the identification of mi RNAs from mesenchymal stem cells ( MSCs), especially from dental pulp, is poorly understood. In this study, dental pulp stem cells ( DPSCs) were characterized in terms of their proliferation and differentiation capacity. Furthermore, 104 known mature mi RNAs were profiled by using real-time PCR. Notably, we observed 19 up-regulated mi RNAs and 29 significantly down-regulated mi RNAs in DPSCs in comparison with bone marrow MSCs ( BM- MSCs). The 19 up-regulated mi RNAs were subjected to ingenuity analysis, which were composed into 25 functional networks. We have chosen top 2 functional networks, which comprised 10 mi RNA (hsa-miR-516a-3p, hsa-miR-125b-1-3p, hsa-miR-221-5p, hsa-miR-7, hsa-miR-584-5p, hsa-miR-190a, hsa-miR-106a-5p, hsa-mir-376a-5p, hsa-mir-377-5p and hsa-let-7f-2-3p). Prediction of target m RNAs and associated biological pathways regulated by each of this mi RNA was carried out. We paid special attention to hsa-miR-516a-3p and hsa-miR-7-5p as these mi RNAs were highly expressed upon validation with q RT- PCR analysis. We further proceeded with loss-of-function analysis with these mi RNAs and we observed that hsa-miR-516a-3p knockdown induced a significant increase in the expression of WNT5A. Likewise, the knockdown of hsa-miR-7-5p increased the expression of EGFR. Nevertheless, further validation revealed the role of WNT5A as an indirect target of hsa-miR-516a-3p. These results provide new insights into the dynamic role of mi RNA expression in DPSCs. In conclusion, using mi RNA signatures in human as a prediction tool will enable us to elucidate the biological processes occurring in DPSCs. [ABSTRACT FROM AUTHOR]

Biochemical networks are at the heart of cellular information processing. These networks contain distinct facets: (i) processing of information from the environment via cascades/pathways along with network regulation and (ii) modification of substrates in different ways, to confer protein functionality, stability and processing. While many studies focus on these factors individually, how they interact and the consequences for cellular systems behaviour are poorly understood. We develop a systems framework for this purpose by examining the interplay of network regulation (canonical feedback and feed-forward circuits) and multisite modification, as an exemplar of substrate modification. Using computational, analytical and semi-analytical approaches, we reveal distinct and unexpected ways in which the substrate modification and network levels combine and the emergent behaviour arising therefrom. This has important consequences for dissecting the behaviour of specific signalling networks, tracing the origins of systems behaviour, inference of networks from data, robustness/evolvability and multi-level engineering of biomolecular networks. Overall, we repeatedly demonstrate how focusing on only one level (say network regulation) can lead to profoundly misleading conclusions about all these aspects, and reveal a number of important consequences for experimental/theoretical/data-driven interrogations of cellular signalling systems.

Simple Summary: The future of cancer immunotherapy relies on a combination of individually targeted therapies. However, a lot of experiments are needed to define the most effective combinations of drugs. A computational and modelling approach could help reduce the number of experiments and suggest optimal treatments to test. This article presents a logical model of T cell activation influenced by immune checkpoints, and explores the effect of these checkpoints, suggests mechanisms that would explain why some treatments might be better suited than others. The model includes not only programmed cell death protein 1 (PD1) and cytotoxic T-lymphocyte-associated protein 4 (CTL4) downstream pathways but also those of other immune checkpoints such as T cell immunoglobulin and ITIM (immunoreceptor tyrosine-based inhibition motif) domain (TIGIT), lymphocyte activation gene 3 (LAG3), T cell immunoglobulin and mucin domain-containing protein 3 (TIM3), cluster of differentiation 226 (CD226), inducible T-cell costimulator (ICOS), and tumour necrosis factor receptors (TNFRs). After the success of the new generation of immune therapies, immune checkpoint receptors have become one important center of attention of molecular oncologists. The initial success and hopes of anti-programmed cell death protein 1 (anti-PD1) and anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4) therapies have shown some limitations since a majority of patients have continued to show resistance. Other immune checkpoints have raised some interest and are under investigation, such as T cell immunoglobulin and ITIM (immunoreceptor tyrosine-based inhibition motif) domain (TIGIT), inducible T-cell costimulator (ICOS), and T cell immunoglobulin and mucin domain-containing protein 3 (TIM3), which appear as promising targets for immunotherapy. To explore their role and study possible synergetic effects of these different checkpoints, we have built a model of T cell receptor (TCR) regulation including not only PD1 and CTLA4, but also other well studied checkpoints (TIGIT, TIM3, lymphocyte activation gene 3 (LAG3), cluster of differentiation 226 (CD226), ICOS, and tumour necrosis factor receptors (TNFRs)) and simulated different aspects of T cell biology. Our model shows good correspondence with observations from available experimental studies of anti-PD1 and anti-CTLA4 therapies and suggest efficient combinations of immune checkpoint inhibitors (ICI). Among the possible candidates, TIGIT appears to be the most promising drug target in our model. The model predicts that signal transducer and activator of transcription 1 (STAT1)/STAT4-dependent pathways, activated by cytokines such as interleukin 12 (IL12) and interferon gamma (IFNG), could improve the effect of ICI therapy via upregulation of Tbet, suggesting that the effect of the cytokines related to STAT3/STAT1 activity is dependent on the balance between STAT1 and STAT3 downstream signalling. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are small non-coding RNAs that regulate translation of mRNA into protein and play a crucial role for almost all biological activities. However, the identification of miRNAs from mesenchymal stem cells (MSCs), especially from dental pulp, is poorly understood. In this study, dental pulp stem cells (DPSCs) were characterized in terms of their proliferation and differentiation capacity. Furthermore, 104 known mature miRNAs were profiled by using real-time PCR. Notably, we observed 19 up-regulated miRNAs and 29 significantly down-regulated miRNAs in DPSCs in comparison with bone marrow MSCs (BM-MSCs). The 19 up-regulated miRNAs were subjected to ingenuity analysis, which were composed into 25 functional networks. We have chosen top 2 functional networks, which comprised 10 miRNA (hsa-miR-516a-3p, hsa-miR-125b-1-3p, hsa-miR-221-5p, hsa-miR-7, hsa-miR-584-5p, hsa-miR-190a, hsa-miR-106a-5p, hsa-mir-376a-5p, hsa-mir-377-5p and hsa-let-7f-2-3p). Prediction of target mRNAs and associated biological pathways regulated by each of this miRNA was carried out. We paid special attention to hsa-miR-516a-3p and hsa-miR-7-5p as these miRNAs were highly expressed upon validation with qRT-PCR analysis. We further proceeded with loss-of-function analysis with these miRNAs and we observed that hsa-miR-516a-3p knockdown induced a significant increase in the expression of WNT5A. Likewise, the knockdown of hsa-miR-7-5p increased the expression of EGFR. Nevertheless, further validation revealed the role of WNT5A as an indirect target of hsa-miR-516a-3p. These results provide new insights into the dynamic role of miRNA expression in DPSCs. In conclusion, using miRNA signatures in human as a prediction tool will enable us to elucidate the biological processes occurring in DPSCs., (© 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)