Elucidating the Role of Wildtype and Variant FGFR2 Structural Dynamics in (Dys)Function and Disorder.

The fibroblast growth factor receptor 2 (FGFR2) gene is one of the most extensively studied genes with many known mutations implicated in several human disorders, including oncogenic ones. Most FGFR2 disease-associated gene mutations are missense mutations that result in constitutive activation of the FGFR2 protein and downstream molecular pathways. Many tertiary structures of the FGFR2 kinase domain are publicly available in the wildtype and mutated forms and in the inactive and activated state of the receptor. The current literature suggests a molecular brake inhibiting the ATP-binding A loop from adopting the activated state. Mutations relieve this brake, triggering allosteric changes between active and inactive states. However, the existing analysis relies on static structures and fails to account for the intrinsic structural dynamics. In this study, we utilize experimentally resolved structures of the FGFR2 tyrosine kinase domain and machine learning to capture the intrinsic structural dynamics, correlate it with functional regions and disease types, and enrich it with predicted structures of variants with currently no experimentally resolved structures. Our findings demonstrate the value of machine learning-enabled characterizations of structure dynamics in revealing the impact of mutations on (dys)function and disorder in FGFR2.

Systematic Identification and Expression Analysis of the Auxin Response Factor (ARF) Gene Family in Ginkgo biloba L.

Auxin participates in various physiological and molecular response-related developmental processes and is a pivotal hormone that regulates phenotypic formation in plants. Auxin response factors (ARFs) are vital transcription factors that mediate downstream auxin signaling by explicitly binding to auxin-responsive genes' promoters. Here, to investigate the possible developmental regulatory functions of ARFs in Ginkgo biloba, through employing comprehensive bioinformatics, we recognized 15 putative GbARF members. Conserved domains and motifs, gene and protein structure, gene duplication, GO enrichment, transcriptome expression profiles, and qRT-PCR all showed that Group I and III members were highly conserved. Among them, GbARF10b and GbARF10a were revealed as transcriptional activators in the auxin response for the development of Ginkgo male flowers through sequences alignment, cis-elements analysis and GO annotation; the results were corroborated for the treatment of exogenous SA. Moreover, the GbARFs expansion occurred predominantly by segmental duplication, and most GbARFs have undergone purifying selection. The Ka/Ks ratio test identified the functional consistence of GbARF2a and GbARF2c, GbARF10b, and GbARF10a in tissue expression profiles and male flower development. In summary, our study established a new research basis for exploring Ginkgo GbARF members' roles in floral organ development and hormone response.

[Diagnostics value and regulatory functions of roinsulin.]

Proinsulin is one of the indicators reflecting the functional activity of the pancreas. In insulin-independent diabetes mellitus the ratio proinsulin / insulin is increased. The review examined the causes of hyperproinsulinemia and the diagnostic value of proinsulin in patients with diabetes mellitus type 1 and 2. The role of proinsulin in the regulation of metabolic pathways and the preservation of the functional activity of cells under physiological conditions, during aging and during pathological processes is discussed. Studies in these areas justify the inclusion of proinsulin in the superfamily of signaling factors. The neuroprotective activity of proinsulin and its potential as a therapeutic tool for neurodegenerative diseases and retinal dystrophy are considered.

Specific functions of the Wnt signaling system in gene regulatory networks throughout the early sea urchin embryo.

Wnt signaling affects cell-fate specification processes throughout embryonic development. Here we take advantage of the well-studied gene regulatory networks (GRNs) that control pregastrular sea urchin embryogenesis to reveal the gene regulatory functions of the entire Wnt-signaling system. Five wnt genes, three frizzled genes, two secreted frizzled-related protein 1 genes, and two Dickkopf genes are expressed in dynamic spatial patterns in the pregastrular embryo of Strongylocentrotus purpuratus. We present a comprehensive analysis of these genes in each embryonic domain. Total functions of the Wnt-signaling system in regulatory gene expression throughout the embryo were studied by use of the Porcupine inhibitor C59, which interferes with zygotic Wnt ligand secretion. Morpholino-mediated knockdown of each expressed Wnt ligand demonstrated that individual Wnt ligands are functionally distinct, despite their partially overlapping spatial expression. They target specific embryonic domains and affect particular regulatory genes. The sum of the effects of blocking expression of individual wnt genes is shown to equal C59 effects. Remarkably, zygotic Wnt-signaling inputs are required for only three general aspects of embryonic specification: the broad activation of endodermal GRNs, the regional specification of the immediately adjacent stripe of ectoderm, and the restriction of the apical neurogenic domain. All Wnt signaling in this pregastrular embryo is short range (and/or autocrine). Furthermore, we show that the transcriptional drivers of wnt genes execute important specification functions in the embryonic domains targeted by the ligands, thus connecting the expression and function of wnt genes by encoded cross-regulatory interactions within the specific regional GRNs.

Biochemistry and regulatory functions of bacterial glucose kinases.

Glucokinases (Glks) are enzymes widely distributed in all three domains of life. They are located at the beginning of the glycolytic pathway and are responsible for the glucose phosphorylation from various phosphate group donors such as ATP, ADP and polyphosphate. So far, there are eight crystallized Glks, and at least one belongs to each of the three reported Glk families. Structural studies have elucidated the mechanism for Glk action and multimerization. Cloning, overexpression and biochemical characterization have demonstrated the wide diversity of these enzymes. As reported for various microorganisms, in addition to their catalytic activity, some Glks, possessing ROK (Repressor Orf Kinases) motifs, also display a regulatory role. This function has been associated to the mechanisms of carbon catabolite regulation, morphological differentiation and antibiotic production. The present review covers the classification, detailed tertiary structure, mechanism of action, biochemical characterization and some regulatory aspects of bacterial Glks.

The hidden messengers: cancer associated fibroblasts-derived exosomal miRNAs as key regulators of cancer malignancy.

Cancer-associated fibroblasts (CAFs), a class of stromal cells in the tumor microenvironment (TME), play a key role in controlling cancer cell invasion and metastasis, immune evasion, angiogenesis, and resistance to chemotherapy. CAFs mediate their activities by secreting soluble chemicals, releasing exosomes, and altering the extracellular matrix (ECM). Exosomes contain various biomolecules, such as nucleic acids, lipids, and proteins. microRNA (miRNA), a 22-26 nucleotide non-coding RNA, can regulate the cellular transcription processes. Studies have shown that miRNA-loaded exosomes secreted by CAFs engage in various regulatory communication networks with other TME constituents. This study focused on the roles of CAF-derived exosomal miRNAs in generating cancer malignant characteristics, including immune modulation, tumor growth, migration and invasion, epithelial-mesenchymal transition (EMT), and treatment resistance. This study thoroughly examines miRNA's dual regulatory roles in promoting and suppressing cancer. Thus, changes in the CAF-derived exosomal miRNAs can be used as biomarkers for the diagnosis and prognosis of patients, and their specificity can be used to develop newer therapies. This review also discusses the pressing problems that require immediate attention, aiming to inspire researchers to explore more novel avenues in this field.

Small noncoding RNA in Streptococci: From regulatory functions to drug development.

Streptococci are a genus of gram-positive coccus of spherical bacteria, including many commensal bacteria and opportunistic pathogens that threaten the public health system. Small noncoding RNAs (sRNAs) are a class of noncoding RNAs regulating gene expression via various regulatory mechanisms, which have been illustrated to play vital roles in regulations of virulence factor expressions. Recent advances in sequencing technology and bioinformatic analysis facilitated discovery of a myriad of sRNAs from pathogenic bacteria, revealing a variety of unique features that contribute to gene expressions and virulence regulations. Although various research studies have reported the regulatory functions of sRNAs in the virulence of bacterial species of the genus Streptococci, the common features of sRNAs in the pathogenesis of Streptococci remain unclear. This blocks the development of novel antistreptococcal antibiotics and antibacterial strategies. Here, we summarize the fundamental roles of Streptococcal sRNAs in pathogenic regulations, which advance mechanistic understanding of streptococcal infection associated diseases. Moreover, we discuss the prospects of sRNA acting as drug targets to combat bacterial antibiotic resistance.

Plant long non-coding RNAs: identification and analysis to unveil their physiological functions.

Eukaryotic genomes encode thousands of RNA molecules; however, only a minimal fraction is translated into proteins. Among the non-coding elements, long non-coding RNAs (lncRNAs) play important roles in diverse biological processes. LncRNAs are associated mainly with the regulation of the expression of the genome; nonetheless, their study has just scratched the surface. This is somewhat due to the lack of widespread conservation at the sequence level, in addition to their relatively low and highly tissue-specific expression patterns, which makes their exploration challenging, especially in plant genomes where only a few of these molecules have been described completely. Recently published high-quality genomes of crop plants, along with new computational tools, are considered promising resources for studying these molecules in plants. This review briefly summarizes the characteristics of plant lncRNAs, their presence and conservation, the different protocols to find these elements, and the limitations of these protocols. Likewise, it describes their roles in different plant physiological phenomena. We believe that the study of lncRNAs can help to design strategies to reduce the negative effect of biotic and abiotic stresses on the yield of crop plants and, in the future, help create fruits and vegetables with improved nutritional content, higher amounts of compounds with positive effects on human health, better organoleptic characteristics, and fruits with a longer postharvest shelf life.

[Advances in the research of microRNA in Orchidaceae].

As a class of small non-coding RNAs, microRNA (miRNA) is widely present and plays important regulatory roles in plant growth, development and stress response. Based on the mechanism of miRNAs in plants, we review the identification of miRNAs in some genera of Orchidaceae, the specific functions of several miRNAs and other relevant studies on miRNAs in the last decade, in order to provide a reference for better understanding function and regulatory network of small RNAs in orchids.

Effectiveness of Different Teaching Resources for Forming the Concept of Magnitude in Older Preschoolers with Varied Levels of Executive Functions.

Background: Studies have shown the great importance of early mathematical development as a predictor of subsequent success, which poses the question of how to organize preschool mathematical education with a view to the children's age characteristics, including their cognitive development. In other words, mathematical concepts and actions should be formed with the help of teaching resources appropriate to the child's development. Objective: To determine the effectiveness of three teaching resources (examples, models, and symbols) in formation of the concept of magnitude in older preschoolers (ages 6-7) with different levels of executive function. Design: Four training programs (with 15 twenty-minute lessons each) were developed and conducted in a formative experiment for older preschoolers with different levels of development of executive functions. The lessons addressed the concept of magnitude (length, area, volume), using different types of teaching resources: exemplars (in traditional and game variants), models, and symbols. The total sample of 116 subjects (44% boys) was divided into 4 groups for each of the programs, plus a control group in which no sessions were conducted. The groups were equalized according to the initial level of development of concepts of magnitude and the level of development of executive functions. Results: There was a statistically significant increase in the quality of mastery of the concept of magnitude in three experimental groups ("symbolic," "traditional," and "traditional with imaginary characters") compared with the control group. The formative effect of the "model-building" program showed no significant differences from the effect of the child's natural development (the control group). We also showed that children with a low level of regulation learned mathematical concepts more effectively with the "symbolic" program; children with a medium level of regulation with the "symbolic" and any variant of the "traditional" program; and children with a high level of regulation with the "symbolic" and "model-building" programs. Conclusion: The findings underline the importance of both the type of teaching resources used and the level of development of voluntary regulation, when teaching mathematics to preschoolers.

Monocyte Gene and Molecular Expression Profiles Suggest Distinct Effector and Regulatory Functions in Beninese HIV Highly Exposed Seronegative Female Commercial Sex Workers.

We have previously reported that the female genital tract (FGT) of Beninese HIV highly-exposed seronegative (HESN) commercial sex workers (CSWs), presented elevated frequencies of a myeloid HLA-DR+CD14+CD11c+ population presenting "tolerogenic" monocyte derived dendritic cells (MoDC) features. In order to assess whether a differential profile of monocytes may be involved in the generation of these genital MoDCs, we have herein characterized the blood monocyte compartment of Beninese HESNs (HIV-uninfected ≥ 10 years CSWs) and relevant controls (HIV-uninfected 2.5-5 years CSWs herein termed "early HESNs"), HIV-infected CSWs, and low-risk HIV-uninfected women from the general population. Transcriptomic analyses by RNA-Seq of total sorted blood monocytes demonstrate that in comparison to the control groups, HESNs present increased expression levels of FCGR2C, FCAR, ITGAX, ITGAM, CR2, CD68, and CD163 genes, associated with effector functions. Moreover, we found increased expression levels of genes associated with protection/control against SHIV/HIV such as CCL3, CCL4, CCL5, BHLHE40, and TNFSF13, as well as with immune regulation such as IL-10, Ahr, CD83, and the orphan nuclear receptor (NR)4A1, NR4A2, and NR4A3. Through multicolor flow cytometry analyses, we noticed that the frequencies of intermediate and non-classical monocyte populations tended to be elevated in the blood of HESNs, and exhibited increased expression levels of effector CD16, CD11c, CD11b, as well as regulatory HLA-G, IL-10, and IFN-α markers when compared to HIV-uninfected women and/or HIV-infected CSWs. This profile is compatible with that previously reported in the FGT of HESNs, and likely confers an enormous advantage in their resistance to HIV infection.

Putative regulatory functions of SNPs associated with bronchial asthma, arterial hypertension and their comorbid phenotype.

Linkage disequilibrium (LD) of single nucleotide polymorphisms (SNPs) of TLR4/AL160272.2 (rs1927914, rs1928298, rs7038716, rs7026297, rs7025144) was estimated in the Slavs of West Siberia. We further investigated an association of SNPs in TLR4/AL160272.2 (rs1927914, rs7038716, rs7025144), SERPINA1 (rs1980616), ATXN2/BRAP (rs11065987), IL2RB (rs2284033), NT5C2 (rs11191582), CARD8 (rs11669386), ANG/RNASE4 (rs1010461), and ABTB2/ САТ (rs2022318) genes with bronchial asthma (BA), arterial hypertension (AH) and their comorbidity. Then, the disease-associated SNPs were annotated in silico in relation to their potential regulatory functions. Strong LD was detected between rs1928298 and rs1927914, as well as rs7026297 and rs7038716 in the Slavs of West Siberia. It was found that the rs1927914 G allele of the TLR4 gene and the rs1980616 C allele of the SERPINA1 gene are associated with the predisposition to BA. These SNPs can affect binding affinity of transcription factors of the Pou and Klf4 families, as well as the expression levels of the TLR4 and SERPINA1 genes. The rs11065987 allele A of the ATXN2/BRAP genes, the rs11669386 A allele of the CARD8 gene, the rs2284033 allele G of the IL2RB gene, and the rs11191582 allele G of the NT5C2 gene were associated with the risk of AH. These variants can alter binding affinity of the Hoxa9, Irf, RORalpha1 and HMG-IY transcription factors, as well as the expression levels of the ALDH2, CARD8, NT5C2, ARL3, and SFXN2 genes in blood cells/vessels/heart, respectively. The risk of developing a comorbid phenotype of AD and AH is associated with the A allele of rs7038716 and the T allele of rs7025144 of the TLR4/AL160272.2 genes, the A allele of rs1010461 of the ANG gene and the C allele of rs2022318 of the ABTB2/CAT genes. Variants rs7038716 and rs7025144 can change the expression levels of the TLR4 gene in blood cells, while rs1010461 and rs2022318 influence the expression levels of the ANG and RNASE4 genes as well as the CAT and ABTB2 genes in blood cells, lungs/vessels/heart.

Long Non-Coding RNAs in Insects.

Only a small subset of all the transcribed RNAs are used as a template for protein translation, whereas RNA molecules that are not translated play a very important role as regulatory non-coding RNAs (ncRNAs). Besides traditionally known RNAs (ribosomal and transfer RNAs), ncRNAs also include small non-coding RNAs (sncRNAs) and long non-coding RNAs (lncRNAs). The lncRNAs, which were initially thought to be junk, have gained a great deal attention because of their regulatory roles in diverse biological processes in animals and plants. Insects are the most abundant and diverse group of animals on this planet. Recent studies have demonstrated the role of lncRNAs in almost all aspects of insect development, reproduction, and genetic plasticity. In this review, we describe the function and molecular mechanisms of the mode of action of different insect lncRNAs discovered up to date.

Role of Parental Attachment Styles in Moderating Interaction Between Parenting Stress and Perceived Infant Characteristics.

By employing the transactional model of development and focusing on the multifactorial nature of parenting, this study aimed to (1) examine whether important risk factors, particularly mothers' insecure attachment styles and parenting stress contribute to the perception of their infants' characteristics and (2) explore whether maternal attachment styles moderate the relationship between parenting stress and perceived infants' characteristics. We recruited 357 mothers (age: 34.23; ± 5.38) who had 1-year-old infants (161 males and 196 females; age: 12.70; ± 1.60 months). All the mothers completed three self-report instruments: Parenting Stress Index-Short Form (PSI-SF), Attachment Style Questionnaire (ASQ), and 1st-Year Inventory (FYI). Although the latter was originally developed to determine the risk for autism in 1-year-olds, it was employed in this study to measure infant's characteristics within two domains: social communication and sensory regulatory functions. Multiple regression analyses revealed that one of the PSI-SF dimensions - specifically the Parent-Child Dysfunctional Interaction - contributed to mothers' perceptions of their children's social communication abilities, whereas the attachment style did not. Other multiple regression analyses showed that all the dimensions of parenting stress - that is, Parenting Distress (PD), Parent-Child Dysfunctional Interaction (PCDI), and Difficult Child (DC) - contributed to mothers' perceptions of their sensory regulatory abilities. The attachment styles, particularly anxious attachment, contributed significantly to a biased perception of these abilities controlled for parenting stress. Mothers reporting high levels of avoidance and high levels of PD viewed their children as less able in the social communicative domain (SC Dom) than if they had low levels of PD. By contrast, when levels of avoidance were low, mothers with high PD perceived their children as less difficult in the SC Dom than those with low levels of PD. Moreover, high avoidance levels influenced how mothers who considered the interaction with their children as difficult perceived them as having greater difficulties in relation to sensory regulatory domain (SR Dom). By contrast, mothers with high levels of anxiety high levels of PD view their children as less able in the SC Dom than if they had low levels of PD. When mothers' levels of anxiety were very low, those with high PD viewed their children as less difficult in the SC Dom in comparison to those with low levels of PD.

The Multiple Roles of B Cells in the Pathogenesis of Sjögren's Syndrome.

Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease characterized by lymphocytic infiltration and tissue destruction of exocrine glands such as salivary glands. Although the formation of ectopic lymphoid tissue in exocrine glands and overproduction of autoantibodies by autoreactive B cells highlight the critical involvement of B cells in disease development, the precise roles of various B cell subsets in pSS pathogenesis remain partially understood. Current studies have identified several novel B cell subsets with multiple functions in pSS, among which autoreactive age-associated B cells, and plasma cells with augmented autoantibody production contribute to the disease progression. In addition, tissue-resident Fc Receptor-Like 4 (FcRL4)+ B cell subset with enhanced pro-inflammatory cytokine production serves as a key driver in pSS patients with mucosa-associated lymphoid tissue (MALT)-lymphomas. Recently, regulatory B (Breg) cells with impaired immunosuppressive functions are found negatively correlated with T follicular helper (Tfh) cells in pSS patients. Further studies have revealed a pivotal role of Breg cells in constraining Tfh response in autoimmune pathogenesis. This review provides an overview of recent advances in the identification of pathogenic B cell subsets and Breg cells, as well as new development of B-cell targeted therapies in pSS patients.

Tr1 Cells as a Key Regulator for Maintaining Immune Homeostasis in Transplantation.

The immune system is composed of effectors and regulators. Type 1 regulatory T (Tr1) cells are classified as a distinct subset of T cells, and they secret high levels of IL-10 but lack the expression of the forkhead box P3 (Foxp3). Tr1 cells act as key regulators in the immune network, and play a central role in maintaining immune homeostasis. The regulatory capacity of Tr1 cells depends on many mechanisms, including secretion of suppressive cytokines, cell-cell contacts, cytotoxicity and metabolic regulation. A breakdown of Tr1-cell-mediated tolerance is closely linked with the pathogenesis of various diseases. Based on this observation, Tr1-cell therapy has emerged as a successful treatment option for a number of human diseases. In this review, we describe an overview of Tr1 cell identification, functions and related molecular mechanisms. We also discuss the current protocols to induce/expand Tr1 cells in vitro for clinical application, and summarize the recent progress of Tr1 cells in transplantation.

Patient safety regulation in the NHS: mapping the regulatory landscape of healthcare.

OBJECTIVES: The current research project sought to map out the regulatory landscape for patient safety in the English National Health Service (NHS). METHOD: We used a systematic desk-based search using a variety of sources to identify the total number of organisations with regulatory influence in the NHS; we researched publicly available documents listing external inspection agencies, participated in advisory consultations with NHS regulatory compliance teams and reviewed the websites of all regulatory agencies. RESULTS: Our mapping revealed over 126 organisations who exert some regulatory influence on NHS provider organisations in addition to 211 Clinical Commissioning Groups. The majority of these organisations set standards and collect data from provider organisations and a considerable number carry out investigations. We found a multitude of overlapping functions and activities. The variability in approach and overlapping functions suggest that there is no overall integrated regulatory approach. CONCLUSION: Regulation potentially provides a variety of benefits in terms of maintaining the safety and quality of care by providing an external perspective on the care being delivered. However, the variability, extent and fragmentation of the regulatory system of the NHS make it hard for regulators to act effectively and places a massive burden on NHS provider organisations. Overlapping regulatory requests may distract locally driven initiatives to improve safety and quality. Further research is needed to understand the full extent of regulatory activity and the true benefits and costs incurred.

Regulatory sRNAs in Cyanobacteria.

As the transcriptional and post-transcriptional regulators of gene expression, small RNAs (sRNAs) play important roles in every domain of life in organisms. It has been discovered gradually that bacteria possess multiple means of gene regulation using RNAs. They have been continuously used as model organisms for photosynthesis, metabolism, biotechnology, evolution, and nitrogen fixation for many decades. Cyanobacteria, one of the most ancient life forms, constitute all kinds of photoautotrophic bacteria and exist in almost any environment on this planet. It is believed that a complex RNA-based regulatory mechanism functions in cyanobacteria to help them adapt to changes and stresses in diverse environments. Although lagging far behind other model microorganisms, such as yeast and Escherichia coli, more and more non-coding regulatory sRNAs have been recognized in cyanobacteria during the past decades. In this article, by focusing on cyanobacterial sRNAs, the approaches for detection and targeting of sRNAs will be summarized, four major mechanisms and regulatory functions will be generalized, eight types of cis-encoded sRNA and four types of trans-encoded sRNAs will be reviewed in detail, and their possible physiological functions will be further discussed.

IL-21 promotes the development of a CD73-positive Vγ9Vδ2 T cell regulatory population.

Vγ9Vδ2 T cells contribute to the immune response against many tumor types through their direct cytotoxic activity and capacity to regulate the biological functions of other immune cells, such as dendritic cells and IFN-γ-producing CD8+ T cells. However, their presence in the tumor microenvironment has also been associated with poor prognosis in breast, colon and pancreatic cancers. Additionally, recent studies demonstrated that cytokines can confer some plasticity to Vγ9Vδ2 T cells and promote their differentiation into cells with regulatory functions. Here, we demonstrated that activation of Vγ9Vδ2 T cells isolated from healthy donors and cultured in the presence of IL-21 favors the emergence of a subpopulation of Vγ9Vδ2 T cells that express the ectonucleotidase CD73 and inhibits T cell proliferation in a CD73/adenosine-dependent manner. This subpopulation produces IL-10 and IL-8 and displays lower effector functions and cytotoxic activity than CD73-negative Vγ9Vδ2 T cells. We also showed, in a syngeneic mouse tumor model, the existence of a tumor-infiltrating γδ T cell subpopulation that produces IL-10 and strongly expresses CD73. Moreover, maturation, IL-12 production and induction of antigen-specific T cell proliferation are impaired in DC co-cultured with IL-21-amplified Vγ9Vδ2 T cells. Altogether, these data indicate that IL-21 promotes Vγ9Vδ2 T cell regulatory functions by favoring the development of an immunosuppressive CD73+ subpopulation. Thus, when present in the tumor microenvironment, IL-21 might negatively impact γδ T cell anti-tumor functions.

A framework to find the logic backbone of a biological network.

BACKGROUND: Cellular behaviors are governed by interaction networks among biomolecules, for example gene regulatory and signal transduction networks. An often used dynamic modeling framework for these networks, Boolean modeling, can obtain their attractors (which correspond to cell types and behaviors) and their trajectories from an initial state (e.g. a resting state) to the attractors, for example in response to an external signal. The existing methods however do not elucidate the causal relationships between distant nodes in the network. RESULTS: In this work, we propose a simple logic framework, based on categorizing causal relationships as sufficient or necessary, as a complement to Boolean networks. We identify and explore the properties of complex subnetworks that are distillable into a single logic relationship. We also identify cyclic subnetworks that ensure the stabilization of the state of participating nodes regardless of the rest of the network. We identify the logic backbone of biomolecular networks, consisting of external signals, self-sustaining cyclic subnetworks (stable motifs), and output nodes. Furthermore, we use the logic framework to identify crucial nodes whose override can drive the system from one steady state to another. We apply these techniques to two biological networks: the epithelial-to-mesenchymal transition network corresponding to a developmental process exploited in tumor invasion, and the network of abscisic acid induced stomatal closure in plants. We find interesting subnetworks with logical implications in these networks. Using these subgraphs and motifs, we efficiently reduce both networks to succinct backbone structures. CONCLUSIONS: The logic representation identifies the causal relationships between distant nodes and subnetworks. This knowledge can form the basis of network control or used in the reverse engineering of networks.