Regulatory Unit Research Articles

Nociceptor–Mast Cell Sensory Clusters as Regulators of Skin Homeostasis

Recent studies revealed the existence of unique functional links between mast cells and nociceptors in the skin. Here, we propose that mast cells and nociceptors form a single regulatory unit in both physiology and disease. In this model, MrgprB2/X2 signaling is a primary mechanism by which mast cells functionally interact with nociceptors to form specialized neuroimmune clusters that regulate pain, inflammation, and itch.

Characteristic Dissection of Xanthomonas oryzae pv. oryzae Responsive MicroRNAs in Rice.

MicroRNAs (miRNAs) are crucial player in plant-pathogen interaction. While the evidence has demonstrated that rice miRNAs mediate immune response to pathogens invasion, the roles of miRNAs on Xanthomonas oryzae pv. oryzae (Xoo) attack remain be in place. Herein, we monitored the responsive changes of rice miRNAs at 0, 8, 24 h across Xoo strain PXO86 infection in its compatible rice variety IR24 and incompatible variety IRBB5 by small RNA sequencing, and the genes targeted by miRNAs were also detected via degradome technology. The faithfulness of sequencing data was validated through quantitative real-time stem-loop reverse transcription-polymerase chain reaction assay. Bioinformatic analysis showed that the differentially expressed miRNAs could be divided into three immunity-related clusters, and 80 regulatory units were emerged in infection process, which comprises 29 differentially expressed known miRNAs and 38 cleaved targets. Furthermore, the miRNA presumptive function of separate immunity cluster in rice-Xoo interplay was confirmed through overexpressing osa-miR164a, osa-miR167d and osa-miR159b, and the disruption of regulatory units, osa-miR164a/OsNAC60, osa-miR167d-5p/OsWD40-174 and osa-miR159b/OsMYBGA, OsLRR-RLK2, OsMPK20-4, may reset rice defense response to Xoo infestation in a controllable manner. These findings provide new insights into the complex roles of characteristic miRNAs and their targets in rice-Xoo interactions.

The NMN Module Conducts Nodule Number Orchestra.

Legumes control nodule number through nodulation and autoregulation of nodulation (AON) pathways. Nodule Inception (NIN) is essential for rhizobial infection and nodule organogenesis in legumes. The GmNINa-miR172c-NNC1 (NMN) module, which consists of two positive regulators, GmNINa and miR172c, and a suppressor, NNC1, integrates both pathways. GmNINa activates miR172c to downregulate NNC1, leading to nodulation, while NNC1 inhibits miR172c expression, forming a negative feedback loop. GmNINa and NNC1 interact with each other and antagonistically fine-tune GmRIC1/RIC2 expression, turning AON on and off. Conversely, activation of AON inhibits GmNINa and miR172c expression, thereby reducing their inhibitory effects on NNC1 to attenuate both nodulation signaling and AON. The NMN module functions not only as an “accelerator” of the nodulation signal to promote nodulation but also as a “brake” on the signal by activating AON to orchestrate nodule number.

Responsive Regulation in Practice: A Review of the International Academic Literature

This research paper presents findings from a broad scoping of the international academic literature on responsive regulation. It builds on a systematic evidence review of peer-reviewed articles published since 1992. The aim of the research paper is to assist executives, managers and front-line workers in regulatory organisations and units who are interested in responsive regulation. It addresses five themes: (1) the evolution of responsive regulation, (2) practical examples of responsive regulation in practice, (3) evidence of the performance of responsive regulation, and (4) the epistemic challenges and (5) ethical challenges that come with this approach to regulatory governance and practice.

Clinical description of measles complications in adults in connection with changes in the functional state of the autonomic nervous system

Aim of the work – to analyze measles complications in adults depending on the severity of the course and to find out their relationship with the functional state of the autonomic nervous system. Results. Clinical manifestations of measles in adults under present conditions retain typical signs, but the feature is the preservation of Filatov–Koplik sign in the period of rashes (77.1 %). In severe course of measles more often (P < 0.01), than with a moderate course, scleroconjunctivitis with eye irritation, hoarseness, hemorrhagic manifestations, nausea, vomiting is recorded, the period of fever is prolonger. In most adult patients, measles had a complicated course (70.5 %), with the spectrum of complications mainly represented by the damage of the respiratory system (61.4 %) and the gastrointestinal tract (43.8 %). The frequency of development of complications and their range clearly depended on the severity of the disease. Complications such as bronchitis (P < 0.05) and pneumonia (P < 0.0001) were more common in patients with severe course of measles. Some patients with a severe course of measles developed such complications as pulmonary edema and left lung atelectasis. The most severe complications from the respiratory organs arose in pregnant women. Gastrointestinal complications such as hepatitis and enteritis were recorded in 43.8 % of patients with measles, and the frequency of their development was also dependent on the severity of the disease (P < 0.01). The Mallory–Weiss syndrome was detected in one patient with a severe course of measles. Analysis of HRV indicators in adult patients with measles showed that in the presence of complications, the functional state of the ANS is characterized by a decrease in power in all regulatory units with the development of imbalance in the direction of sympathicotonia, compared with healthy people (P < 0.01). In patients with a complicated course of measles, indicators that characterize the total power of vegetative regulation, the parameter characterizing the humoral effects on the ANS (VLF), were lower (P < 0.05), and part of the sympathetic effects in the general spectrum of vegetative regulation is higher (P < 0.05) than in patients without complications of this infection. Conclusions. Clinical manifestations of measles in adults under present conditions remain typical, but in most adult patients (70.5 %) measles has a complicated character. The complications from the respiratory system (61.4 %) and the gastrointestinal tract (43.8 %) are often recorded, the frequency and spectrum of which depend on the severity of the disease. Complications from the nervous system and the organs of vision develop in single adult patients with severe course of measles. Disorders of ANS functional state play a role in depending of measles complications in adults. In the presence of complications, the functional state of ANS is characterized by a decrease in power in all regulatory units with the development of imbalance in the direction of sympathicotonia.

The distributions of protein coding genes within chromatin domains in relation to human disease

BackgroundOur understanding of the nuclear chromatin structure has increased hugely during the last years mainly as a consequence of the advances in chromatin conformation capture methods like Hi-C. The unprecedented resolution of genome-wide interaction maps shows functional consequences that extend the initial thought of an efficient DNA packaging mechanism: gene regulation, DNA repair, chromosomal translocations and evolutionary rearrangements seem to be only the peak of the iceberg. One key concept emerging from this research is the topologically associating domains (TADs) whose functional role in gene regulation and their association with disease is not fully untangled.ResultsWe report that the lower the number of protein coding genes inside TADs, the higher the tendency of those genes to be associated with disease (p-value = 4 × 10^{-54}). Moreover, housekeeping genes are less associated with disease than other genes. Accordingly, they are depleted in TADs containing less than three protein coding genes (p-value = 3.9 × 10^{-34}). We observed that TADs with higher ratios of enhancers versus genes contained higher numbers of disease-associated genes. We interpret these results as an indication that sharing enhancers among genes reduces their involvement in disease. Larger TADs would have more chances to accommodate many genes and select for enhancer sharing along evolution.ConclusionsGenes associated with human disease do not distribute randomly over the TADs. Our observations suggest general rules that confer functional stability to TADs, adding more evidence to the role of TADs as regulatory units.

Gene Regulatory Network of Dorsolateral Prefrontal Cortex: a Master Regulator Analysis of Major Psychiatric Disorders.

Despite the strong genetic component of psychiatric disorders, traditional genetic studies have failed to find individual genes of large effect size. Thus, alternative methods, using bioinformatics, have been proposed to solve these biological puzzles. Of these, here we employ systems biology-based approaches to identify potential master regulators (MRs) of bipolar disorder (BD), schizophrenia (SZ), and major depressive disorder (MDD), their association with biological processes and their capacity to differentiate disorders' phenotypes. High-throughput gene expression data was used to reconstruct standard human dorsolateral prefrontal cortex regulatory transcriptional network, which was then queried for regulatory units and MRs associated with the psychiatric disorders of interest. Furthermore, the activity status (active or repressed) of MR candidates was obtained and used in cluster analysis to characterize disease phenotypes. Finally, we explored the biological processes modulated by the MRs using functional enrichment analysis. Thirty-one, thirty-four, and fifteen MR candidates were identified in BD, SZ, and MDD, respectively. The activity state of these MRs grouped the illnesses in three clusters: MDD only, mostly BD, and a third one with BD and SZ. While BD and SZ share several biological processes related to ion transport and homeostasis, synapse, and immune function, SZ showed peculiar enrichment of processes related to cytoskeleton and neuronal structure. Meanwhile, MDD presented mostly processes related to glial development and fatty acid metabolism. Our findings suggest notable differences in functional enrichment between MDD and BD/SZ. Furthermore, similarities between BD and SZ may impose particular challenges in attempts to discriminate these pathologies based solely on their transcriptional profiles. Nevertheless, we believe that systems-oriented approaches are promising strategies to unravel the pathophysiology peculiarities underlying mental illnesses and reveal therapeutic targets.

CRUP: a comprehensive framework to predict condition-specific regulatory units

We present the software Condition-specific Regulatory Units Prediction (CRUP) to infer from epigenetic marks a list of regulatory units consisting of dynamically changing enhancers with their target genes. The workflow consists of a novel pre-trained enhancer predictor that can be reliably applied across cell types and species, solely based on histone modification ChIP-seq data. Enhancers are subsequently assigned to different conditions and correlated with gene expression to derive regulatory units. We thoroughly test and then apply CRUP to a rheumatoid arthritis model, identifying enhancer-gene pairs comprising known disease genes as well as new candidate genes.

English

In Ethiopia, chickpea is an important grain legume next to faba bean and common bean. Quality seed production and associated technologies could be mentioned among the major challenges that limit chickpea production and productivity in Ethiopia. This study was conducted to assess the quality of seeds at different generation classes as obtained from various sources that would contribute an estimate of more than half the chickpea seed suppliers. Thirty one seed samples taken from ten different formal seed sources and four seed classes were used to test physical, physiological and seed health parameters. The result of the laboratory study indicated that seed sources and classes have affected highly significantly the moisture content and hundred seed weight. Correlation analysis showed that seed purity had positive and highly significantly influenced standard germination, vigor index, seedling dry weight and hundred seed weight. Similarly, vigor index was correlated positively and highly significantly with speed of standard germination and root length. Considering seed health as standard quality parameters showed that no seed sources and classes met the standards set by the national seed quality. The seed regulatory unit should be considered in the future in enhancing the seed standard levels and on undermined factors associated to seed health. Key words: Physical purity, seed class, seed health, seed vigor. &nbsp;

Epigenome editing strategies for the functional annotation of CTCF insulators

The human genome is folded into regulatory units termed ‘topologically-associated domains’ (TADs). Genome-wide studies support a global role for the insulator protein CTCF in mediating chromosomal looping and the topological constraint of TAD boundaries. However, the impact of individual insulators on enhancer-gene interactions and transcription remains poorly understood. Here, we investigate epigenome editing strategies for perturbing individual CTCF insulators and evaluating consequent effects on genome topology and transcription. We show that fusions of catalytically-inactive Cas9 (dCas9) to transcriptional repressors (dCas9-KRAB) and DNA methyltransferases (dCas9-DNMT3A, dCas9-DNMT3A3L) can selectively displace CTCF from specific insulators, but only when precisely targeted to the cognate motif. We further demonstrate that stable, partially-heritable insulator disruption can be achieved through combinatorial hit-and-run epigenome editing. Finally, we apply these strategies to simulate an insulator loss mechanism implicated in brain tumorigenesis. Our study provides strategies for stably modifying genome organization and gene activity without altering the underlying DNA sequence.

Integrated transcriptomics reveals master regulators of lung adenocarcinoma and novel repositioning of drug candidates.

BackgroundLung adenocarcinoma is the major cause of cancer‐related deaths in the world. Given this, the importance of research on its pathophysiology and therapy remains a key health issue. To assist in this endeavor, recent oncology studies are adopting Systems Biology approaches and bioinformatics to analyze and understand omics data, bringing new insights about this disease and its treatment.MethodsWe used reverse engineering of transcriptomic data to reconstruct nontumorous lung reference networks, focusing on transcription factors (TFs) and their inferred target genes, referred as regulatory units or regulons. Afterwards, we used 13 case‐control studies to identify TFs acting as master regulators of the disease and their regulatory units. Furthermore, the inferred activation patterns of regulons were used to evaluate patient survival and search drug candidates for repositioning.ResultsThe regulatory units under the influence of ATOH8, DACH1, EPAS1, ETV5, FOXA2, FOXM1, HOXA4, SMAD6, and UHRF1 transcription factors were consistently associated with the pathological phenotype, suggesting that they may be master regulators of lung adenocarcinoma. We also observed that the inferred activity of FOXA2, FOXM1, and UHRF1 was significantly associated with risk of death in patients. Finally, we obtained deptropine, promazine, valproic acid, azacyclonol, methotrexate, and ChemBridge ID compound 5109870 as potential candidates to revert the molecular profile leading to decreased survival.ConclusionUsing an integrated transcriptomics approach, we identified master regulator candidates involved with the development and prognostic of lung adenocarcinoma, as well as potential drugs for repurposing.

474 Inherited duplications of PPP2R3B promote naevi and melanoma via a novel C21orf91-driven proliferative phenotype

The majority of the heredity of melanoma remains unexplained, however inherited copy number changes have not yet been systematically studied. The genetic environment is highly relevant to treatment stratification, and new gene discovery is therefore desirable. Using an unbiased whole genome screening approach for copy number we identify here a novel melanoma predisposing factor, familial duplications of gene PPP2R3B, encoding a regulatory unit of critical phosphatase PP2A. Significant correlation between expression of PPP2R3B in tumour tissue and survival in a large melanoma cohort was confirmed, and associated with a non-immunological expression profile. Mechanistically, construction and extensive characterization of a stable, inducible cellular model for PPP2R3B overexpression revealed induction of pigment cell switching towards proliferation and away from migration. Importantly, this was independent of the known microphthalmia-associated transcription factor (MITF)-controlled pigment cell phenotype switch, and was instead driven by uncharacterised gene C21orf91. Bioinformatic studies point to C21orf91 as a novel target of MITF, and therefore a potential hub in the control of phenotype switching in melanoma. This study identifies novel germline copy number variants in PPP2R3B predisposing to melanocytic neoplasia, and uncovers a new potential therapeutic target C21orf91 in the control of pigment cell proliferation.

Systemic acquired resistance networks amplify airborne defense cues

Salicylic acid (SA)-mediated innate immune responses are activated in plants perceiving volatile monoterpenes. Here, we show that monoterpene-associated responses are propagated in feed-forward loops involving the systemic acquired resistance (SAR) signaling components pipecolic acid, glycerol-3-phosphate, and LEGUME LECTIN-LIKE PROTEIN1 (LLP1). In this cascade, LLP1 forms a key regulatory unit in both within-plant and between-plant propagation of immunity. The data integrate molecular components of SAR into systemic signaling networks that are separate from conventional, SA-associated innate immune mechanisms. These networks are central to plant-to-plant propagation of immunity, potentially raising SAR to the population level. In this process, monoterpenes act as microbe-inducible plant volatiles, which as part of plant-derived volatile blends have the potential to promote the generation of a wave of innate immune signaling within canopies or plant stands. Hence, plant-to-plant propagation of SAR holds significant potential to fortify future durable crop protection strategies following a single volatile trigger.

A Stochastic Multiscale Model of Cardiac Thin Filament Activation Using Brownian-Langevin Dynamics

We use Brownian-Langevin dynamics principles to derive a coarse-graining multiscale myofilament model that can describe the thin-filament activation process during contraction. The model links atomistic molecular simulations of protein-protein interactions in the thin-filament regulatory unit to sarcomere-level activation dynamics. We first calculate the molecular interaction energy between tropomyosin and actin surface using Brownian dynamics simulations. This energy profile is then generalized to account for the observed tropomyosin transitions between its regulatory stable states. The generalized energy landscape then served as a basis for developing a filament-scale model using Langevin dynamics. This integrated analysis, spanning molecular to thin-filament scales, is capable of tracking the events of the tropomyosin conformational changes as it moves over the actin surface. The tropomyosin coil with flexible overlap regions between adjacent tropomyosins is represented in the model as a system of coupled stochastic ordinary differential equations. The proposed multiscale approach provides a more detailed molecular connection between tropomyosin dynamics, the trompomyosin-actin interaction-energy landscape, and the generated force by the sarcomere.

High-speed AFM reveals subsecond dynamics of cardiac thin filaments upon Ca2+ activation and heavy meromyosin binding

High-speed atomic force microscopy (HS-AFM) can be used to study dynamic processes with real-time imaging of molecules within 1- to 5-nm spatial resolution. In the current study, we evaluated the 3-state model of activation of cardiac thin filaments (cTFs) isolated as a complex and deposited on a mica-supported lipid bilayer. We studied this complex for dynamic conformational changes 1) at low and high [Ca2+] (pCa 9.0 and 4.5), and 2) upon myosin binding to the cTF in the nucleotide-free state or in the presence of ATP. HS-AFM was used to directly visualize the tropomyosin-troponin complex and Ca2+-induced tropomyosin movements accompanied by structural transitions of actin monomers within cTFs. Our data show that cTFs at relaxing or activating conditions are not ultimately in a blocked or activated state, respectively, but rather the combination of states with a prevalence that is dependent on the [Ca2+] and the presence of weakly or strongly bound myosin. The weakly and strongly bound myosin induce similar changes in the structure of cTFs as confirmed by the local dynamical displacement of individual tropomyosin strands in the center of a regulatory unit of cTF at the relaxed and activation conditions. The displacement of tropomyosin at the relaxed conditions had never been visualized directly and explains the ability of myosin binding to TF at the relaxed conditions. Based on the ratios of nonactivated and activated segments within cTFs, we proposed a mechanism of tropomyosin switching from different states that includes both weakly and strongly bound myosin.

Impact of genome architecture on the functional activation and repression of Hox regulatory landscapes

BackgroundThe spatial organization of the mammalian genome relies upon the formation of chromatin domains of various scales. At the level of gene regulation in cis, collections of enhancer sequences define large regulatory landscapes that usually match with the presence of topologically associating domains (TADs). These domains often contain ranges of enhancers displaying similar or related tissue specificity, suggesting that in some cases, such domains may act as coherent regulatory units, with a global on or off state. By using the HoxD gene cluster, which specifies the topology of the developing limbs via highly orchestrated regulation of gene expression, as a paradigm, we investigated how the arrangement of regulatory domains determines their activity and function.ResultsProximal and distal cells in the developing limb express different levels of Hoxd genes, regulated by flanking 3′ and 5′ TADs, respectively. We characterized the effect of large genomic rearrangements affecting these two TADs, including their fusion into a single chromatin domain. We show that, within a single hybrid TAD, the activation of both proximal and distal limb enhancers globally occurred as when both TADs are intact. However, the activity of the 3′ TAD in distal cells is generally increased in the fused TAD, when compared to wild type where it is silenced. Also, target gene activity in distal cells depends on whether or not these genes had previously responded to proximal enhancers, which determines the presence or absence of H3K27me3 marks. We also show that the polycomb repressive complex 2 is mainly recruited at the Hox gene cluster and can extend its coverage to far-cis regulatory sequences as long as confined to the neighboring TAD structure.ConclusionsWe conclude that antagonistic limb proximal and distal enhancers can exert their specific effects when positioned into the same TAD and in the absence of their genuine target genes. We also conclude that removing these target genes reduced the coverage of a regulatory landscape by chromatin marks associated with silencing, which correlates with its prolonged activity in time.

Copper relay path through the N-terminus of Wilson disease protein, ATP7B

In human cells, copper (Cu) ions are transported by the cytoplasmic Cu chaperone Atox1 to the Wilson disease protein (ATP7B) in the Golgi for loading of Cu-dependent enzymes. ATP7B is a membrane-spanning protein which, in contrast to non-mammalian homologs, has six cytoplasmic metal-binding domains (MBDs). To address the reason for multiple MBDs, we introduced strategic mutations in which one, two or three MBDs had been blocked for Cu binding via cysteine-to-serine mutations (but all six MBDs are present in all) in a yeast system that probes Cu flow through Atox1 and ATP7B. The results, combined with earlier work, support a mechanistic model in which MBD1-3 forms a regulatory unit of ATP7B Cu transport. Cu delivery via Atox1 to this unit, followed by loading of Cu in MBD3, promotes release of inhibitory interactions. Whereas the Cu site in MBD4 can be mutated without a large effect, an intact Cu site in either MBD5 or MBD6 is required for Cu transport. All MBDs, expressed as single-domain proteins, can replace Atox1 and deliver Cu to full-length ATP7B. However, only MBD6 can deliver Cu to truncated ATP7B where all six MBDs are removed, suggesting a docking role for this structural unit.

The freshwater biome gradient framework: predicting macroscale properties based on latitude, altitude, and precipitation

AbstractUnderstanding global ecological patterns and processes, from biogeochemical to biogeographical, requires broad‐scale macrosystems context for comparing and contrasting ecosystems. Climate gradients (precipitation and temperature) and other continental‐scale patterns shape freshwater environments due to their influences on terrestrial environments and their direct and indirect effects on the abiotic and biotic characteristics of lakes, streams, and wetlands. We combined literature review, analyses of open access data, and logical argument to assess abiotic and biotic characters of freshwater systems across gradients of latitude and elevation that drive precipitation, temperature, and other variability. We explored the predictive value of analyzing patterns in freshwater ecosystems at the global macrosystems scale. We found many patterns based on climate, particularly those dependent upon hydrologic characteristics and linked to characteristics of terrestrial biomes. For example, continental waters of dry areas will generally be widely dispersed and have higher probability of drying and network disconnection, greater temperatures, greater inorganic turbidity, greater salinity, and lower riparian canopy cover relative to areas with high precipitation. These factors will influence local community composition and ecosystem rates. Enough studies are now available at the continental or global scale to start to characterize patterns under a coherent conceptual framework, though considerable gaps exist in the tropics and less developed regions. We present illustrative global‐scale trends of abiotic, biotic, and anthropogenic impacts in freshwater ecosystems across gradients of precipitation and temperature to further understanding of broad‐scale trends and to aid prediction in the face of global change. We view freshwater systems as occurring across arrays of multiple gradients (including latitude, altitude, and precipitation) rather than areas with specific boundaries. While terrestrial biomes capture some variability along these gradients that influence freshwaters, other features such as, slope, geology, and historical glaciation also influence freshwaters. Our conceptual framework is not so much a single hypothesis as a way to logically characterize patterns in freshwaters at scales relevant to (1) evolutionary processes that give rise to freshwater biodiversity, (2) regulatory units that influence freshwater ecosystems, and (3) the current scope of anthropogenic impacts on freshwaters and the vital ecosystem services they provide.

Abstract 5040: Involvement of PI3K/Akt pathway in cadmium triggered aggressive prostate cancer

Abstract Cadmium (Cd) has been implicated in cancer development and classified as a type I carcinogen by the International Agency for Cancer Research. The etiology of prostate cancer development is associated with multitude of causative risk factors including exposure to cadmium. However, the molecular mechanisms associated with Cd-induced prostate cancer remain elusive. This study provides evidence that PI3K/Akt signaling is a major molecular pathway involved in Cd induced malignant transformation of normal prostate epithelial cells. Functionally, Cd exposure induced aggressive behavior as indicated by increased proliferation, migration and invasion in Cd-RWPE1 cells compared to parental RWPE1. PI3K/Akt pathway is constitutively activated in prostate cancer driving the most aggressive forms of cancer and metastasis. Consistent with these findings, the RT2 PCR array analysis of 84 genes involved in the PI3K/Akt pathway revealed induction of gene expression in catalytic units (P110α, Akt, mTOR, NFKB1, RAF etc.) with a concomitant reduction in expression of regulatory units (PIK3R1, PIK3R2, PTEN etc.) of the PI3K/Akt pathway in Cd-RWPE1 cells compared to parental RWPE1. This was confirmed by individual quantitative real-time PCR analysis using TaqMan gene expression assay probes. Effect of Cd on the translation of the PI3K/Akt pathway genes was examined by immunoblot assays. Gene Set Enrichment Analysis (GSEA) for differentially expressed genes in Cd-RWPE1 showed 5 overlapping pathways that were enriched in Cd-treated cells (Cd-RWPE1) and negatively correlated with parental RWPE1. The overlapping pathways include KEGG Apoptosis pathway (ES=0.56, NES=1), KEGG ERBB pathway (ES=0.25, NES=1), KEGG MAPK pathway (ES=0.48, NES=1), KEGG Pathways in cancer (ES=0.33, NES=1) and KEGG Prostate Cancer pathway (ES=0.35, NES=1). Interestingly, all these pathways are implicated in prostate cancer progression and metastasis. We randomly selected up- and down-regulated genes from the PI3K/Akt pathway in PCR array and performed profile analysis in a prostate adenocarcinoma data set (n=534) from the TCGA/GDC data base. We observed upregulation of the oncogenes along with downregulation of tumor suppressors in prostate cancer compared to normal prostate samples. Taken together, these data reveal that Cd exposure induced aggressive malignant characteristics in normal prostate epithelial cells via modulation of the PI3K/Akt signaling pathway. Understanding the molecular mechanisms involved in the malignant transformation of normal prostate epithelial cells may help develop optimal therapeutic strategies for advanced prostate cancer. Citation Format: Priyanka Kulkarni, Pritha Dasgupta, Nadeem S. Bhat, Yutaka Hashimoto, Sharanjot Saini, Altaf A. Dar, Varahram Shahryari, Marisa Shiina, Soichiro Yamamura, Yuichiro Tanaka, Rajvir Dahiya, Shahana Majid. Involvement of PI3K/Akt pathway in cadmium triggered aggressive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5040.

RTNduals: an R/Bioconductor package for analysis of co-regulation and inference of dual regulons.

Transcription factors (TFs) are key regulators of gene expression, and can activate or repress multiple target genes, forming regulatory units, or regulons. Understanding downstream effects of these regulators includes evaluating how TFs cooperate or compete within regulatory networks. Here we present RTNduals, an R/Bioconductor package that implements a general method for analyzing pairs of regulons. RTNduals identifies a dual regulon when the number of targets shared between a pair of regulators is statistically significant. The package extends the RTN (Reconstruction of Transcriptional Networks) package, and uses RTN transcriptional networks to identify significant co-regulatory associations between regulons. The Supplementary Information reports two case studies for TFs using the METABRIC and TCGA breast cancer cohorts. RTNduals is written in the R language, and is available from the Bioconductor project at http://bioconductor.org/packages/RTNduals/. Supplementary data are available at Bioinformatics online.