Omics-Based Strategies in Precision Medicine: Toward a Paradigm Shift in Inborn Errors of Metabolism Investigations.

Int J Mol Sci. 2016;17(9)

Authors: Tebani A, Afonso C, Marret S, Bekri S

Abstract
The rise of technologies that simultaneously measure thousands of data points represents the heart of systems biology. These technologies have had a huge impact on the discovery of next-generation diagnostics, biomarkers, and drugs in the precision medicine era. Systems biology aims to achieve systemic exploration of complex interactions in biological systems. Driven by high-throughput omics technologies and the computational surge, it enables multi-scale and insightful overviews of cells, organisms, and populations. Precision medicine capitalizes on these conceptual and technological advancements and stands on two main pillars: data generation and data modeling. High-throughput omics technologies allow the retrieval of comprehensive and holistic biological information, whereas computational capabilities enable high-dimensional data modeling and, therefore, accessible and user-friendly visualization. Furthermore, bioinformatics has enabled comprehensive multi-omics and clinical data integration for insightful interpretation. Despite their promise, the translation of these technologies into clinically actionable tools has been slow. In this review, we present state-of-the-art multi-omics data analysis strategies in a clinical context. The challenges of omics-based biomarker translation are discussed. Perspectives regarding the use of multi-omics approaches for inborn errors of metabolism (IEM) are presented by introducing a new paradigm shift in addressing IEM investigations in the post-genomic era.

PMID: 27649151 [PubMed - as supplied by publisher]

Translating MicroRNA Biology in Pulmonary Hypertension: It Will Take More Than "miR" Words.

Am J Respir Crit Care Med. 2016 Sep 20;

Authors: Chun HJ, Bonnet S, Chan SY

Abstract
Pulmonary hypertension (PH) is an enigmatic vascular disease with complex molecular origins, leading to right ventricular failure and often death. Recent studies have implicated the pervasive actions of microRNAs in the pulmonary vasculature and the right ventricle as essential to the development of PH. MicroRNAs are small, non-protein coding RNA molecules that negative regulate gene expression. Because greater than 5,500 microRNA molecules have been predicted or verified to be encoded by the human genome, we are still at the inception of our mechanistic understanding of how all of these factors, either singly or in combination, control pulmonary vascular function in health and disease. As insights into the biology of these pleiotropic molecules grow, we move closer to applying this biology in novel clinical diagnostic and therapeutic strategies in PH. In this review, we will discuss the recent molecular data of specific microRNAs in the pulmonary vasculature and methods by which we can begin to understand the systems biology of these pleiotropic molecules on overall pulmonary vascular pathophenotypes. We will also discuss advancing applications of quantifying plasma-based circulating microRNAs for development of new biomarkers in PH. Finally, we will examine the principles of therapeutic targeting of microRNAs in PH as well as the specialized challenges in such drug development. As such, we plan to illustrate the promise, challenges, and current limitations of leveraging microRNA biology to understand and manage pulmonary vascular disease.

PMID: 27648944 [PubMed - as supplied by publisher]

Molecular Adjuvants for DNA Vaccines.

Curr Issues Mol Biol. 2016 Sep 20;22:17-40

Authors: Li L, Petrovsky N

Abstract
Poor immunogenicity remains the single biggest obstacle to human DNA vaccines achieving their potential. Strategies to improve DNA vaccine efficacy include codon optimization, transfection reagents, electroporation, vaccine adjuvants or combination with a protein or vector boost. Increased understanding of molecular events driving innate and adaptive immune responses has assisted development of molecular adjuvants for DNA vaccine use. Such adjuvants comprise plasmid-encoded signalling molecules including cytokines, chemokines, immune costimulatory molecules, toll-like receptor agonists or inhibitors of immune suppressive pathways. New approaches including gene knockdown, epigenetics and systems biology have also contributed to an increased range of molecular adjuvant options. This review explores current and future trends in vaccine design including the latest molecular adjuvants for enhanced DNA vaccine efficacy.

PMID: 27648581 [PubMed - as supplied by publisher]

Quantitative proteomics and terminomics to elucidate the role of ubiquitination and proteolysis in adaptive immunity.

Philos Trans A Math Phys Eng Sci. 2016 Oct 28;374(2079)

Authors: Klein T, Viner RI, Overall CM

Abstract
Adaptive immunity is the specialized defence mechanism in vertebrates that evolved to eliminate pathogens. Specialized lymphocytes recognize specific protein epitopes through antigen receptors to mount potent immune responses, many of which are initiated by nuclear factor-kappa B activation and gene transcription. Most, if not all, pathways in adaptive immunity are further regulated by post-translational modification (PTM) of signalling proteins, e.g. phosphorylation, citrullination, ubiquitination and proteolytic processing. The importance of PTMs is reflected by genetic or acquired defects in these pathways that lead to a dysfunctional immune response. Here we discuss the state of the art in targeted proteomics and systems biology approaches to dissect the PTM landscape specifically regarding ubiquitination and proteolysis in B- and T-cell activation. Recent advances have occurred in methods for specific enrichment and targeted quantitation. Together with improved instrument sensitivity, these advances enable the accurate analysis of often rare PTM events that are opaque to conventional proteomics approaches, now rendering in-depth analysis and pathway dissection possible. We discuss published approaches, including as a case study the profiling of the N-terminome of lymphocytes of a rare patient with a genetic defect in the paracaspase protease MALT1, a key regulator protease in antigen-driven signalling, which was manifested by elevated linear ubiquitination.This article is part of the themed issue 'Quantitative mass spectrometry'.

PMID: 27644975 [PubMed - as supplied by publisher]

Simulation of the M13 life cycle I: Assembly of a genetically-structured deterministic chemical kinetic simulation.

Virology. 2016 Sep 16;

Authors: Smeal SW, Schmitt MA, Pereira RR, Prasad A, Fisk JD

Abstract
To expand the quantitative, systems level understanding and foster the expansion of the biotechnological applications of the filamentous bacteriophage M13, we have unified the accumulated quantitative information on M13 biology into a genetically-structured, experimentally-based computational simulation of the entire phage life cycle. The deterministic chemical kinetic simulation explicitly includes the molecular details of DNA replication, mRNA transcription, protein translation and particle assembly, as well as the competing protein-protein and protein-nucleic acid interactions that control the timing and extent of phage production. The simulation reproduces the holistic behavior of M13, closely matching experimentally reported values of the intracellular levels of phage species and the timing of events in the M13 life cycle. The computational model provides a quantitative description of phage biology, highlights gaps in the present understanding of M13, and offers a framework for exploring alternative mechanisms of regulation in the context of the complete M13 life cycle.

PMID: 27644585 [PubMed - as supplied by publisher]

Resolving coiled shapes reveals new reorientation behaviors in C. elegans.

Elife. 2016;5

Authors: Broekmans OD, Rodgers JB, Ryu WS, Stephens GJ

Abstract
We exploit the reduced space of C. elegans postures to develop a novel tracking algorithm which captures both simple shapes and also self-occluding coils, an important, yet unexplored, component of 2D worm behavior. We apply our algorithm to show that visually complex, coiled sequences are a superposition of two simpler patterns: the body wave dynamics and a head-curvature pulse. We demonstrate the precise Ω-turn dynamics of an escape response and uncover a surprising new dichotomy in spontaneous, large-amplitude coils; deep reorientations occur not only through classical Ω-shaped postures but also through larger postural excitations which we label here as δ-turns. We find that omega and delta turns occur independently, suggesting a distinct triggering mechanism, and are the serpentine analog of a random left-right step. Finally, we show that omega and delta turns occur with approximately equal rates and adapt to food-free conditions on a similar timescale, a simple strategy to avoid navigational bias.

PMID: 27644113 [PubMed - as supplied by publisher]

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Non-linear interactions between candidate genes of myocardial infarction revealed in mRNA expression profiles.

BMC Genomics. 2016;17(1):738

Authors: Hartmann K, Seweryn M, Handleman SK, Rempała GA, Sadee W

Abstract
BACKGROUND: Alterations in gene expression are key events in disease etiology and risk. Poor reproducibility in detecting differentially expressed genes across studies suggests individual genes may not be sufficiently informative for complex diseases, such as myocardial infarction (MI). Rather, dysregulation of the 'molecular network' may be critical for pathogenic processes. Such a dynamic network can be built from pairwise non-linear interactions.
RESULTS: We investigate non-linear interactions represented in mRNA expression profiles that integrate genetic background and environmental factors. Using logistic regression, we test the association of individual GWAS-based candidate genes and non-linear interaction terms (between these mRNA expression levels) with MI. Based on microarray data in CATHGEN (CATHeterization in GENetics) and FHS (Framingham Heart Study), we find individual genes and pairs of mRNAs, encoded by 41 MI candidate genes, with significant interaction terms in the logistic regression model. Two pairs replicate between CATHGEN and FHS (CNNM2|GUCY1A3 and CNNM2|ZEB2). Analysis of RNAseq data from GTEx (Genotype-Tissue Expression) shows that 20 % of these disease-associated RNA pairs are co-expressed, further prioritizing significant interactions. Because edges in sparse co-expression networks formed solely by the 41 candidate genes are unlikely to represent direct physical interactions, we identify additional RNAs as links between network pairs of candidate genes. This approach reveals additional mRNAs and interaction terms significant in the context of MI, for example, the path CNNM2|ACSL5|SCARF1|GUCY1A3, characterized by the common themes of magnesium and lipid processing.
CONCLUSIONS: The results of this study support a role for non-linear interactions between genes in MI and provide a basis for further study of MI systems biology. mRNA expression profiles encoded by a limited number of candidate genes yield sparse networks of MI-relevant interactions that can be expanded to include additional candidates by co-expression analysis. The non-linear interactions observed here inform our understanding of the clinical relevance of gene-gene interactions in the pathophysiology of MI, while providing a new strategy in developing clinical biomarker panels.

PMID: 27640124 [PubMed - as supplied by publisher]

Modulating carbohydrate-protein interactions through glycoengineering of monoclonal antibodies to impact cancer physiology.

Curr Opin Struct Biol. 2016 Sep 14;40:104-111

Authors: Chiang AW, Li S, Spahn PN, Richelle A, Kuo CC, Samoudi M, Lewis NE

Abstract
Diverse glycans on proteins impact cell and organism physiology, along with drug activity. Since many protein-based biotherapeutics are glycosylated and these glycans have biological activity, there is a desire to engineer glycosylation for recombinant protein-based biotherapeutics. Engineered glycosylation can impact the recombinant protein efficacy and also influence many cell pathways by first changing glycan-protein interactions and consequently modulating disease physiologies. However, its complexity is enormous. Recent advances in glycoengineering now make it easier to modulate protein-glycan interactions. Here, we discuss how engineered glycans contribute to therapeutic monoclonal antibodies (mAbs) in the treatment of cancers, how these glycoengineered therapeutic mAbs affect the transformed phenotypes and downstream cell pathways. Furthermore, we suggest how systems biology can help in the next generation mAb glycoengineering process by aiding in data analysis and guiding engineering efforts to tailor mAb glycan and ultimately drug efficacy, safety and affordability.

PMID: 27639240 [PubMed - as supplied by publisher]

GPS for QSP: A Summary of the ACoP6 Symposium on Quantitative Systems Pharmacology and a Stage for Near-Term Efforts in the Field.

CPT Pharmacometrics Syst Pharmacol. 2016 Sep 17;

Authors: Musante CJ, Abernethy DR, Allerheiligen SR, Lauffenburger DA, Zager MG

Abstract
Quantitative Systems Pharmacology (QSP) is experiencing increased application in the drug discovery and development process. Like its older sibling, systems biology, the QSP field is comprised of a mix of established disciplines and methods, from molecular biology to engineering to pharmacometrics. As a result, there exist critical segments of the discipline that differ dramatically in approach and a need to bring these groups together toward a common goal.

PMID: 27639191 [PubMed - as supplied by publisher]

A decade of Central and Eastern European Proteomic Conference (CEEPC): Credibility, cohesion and vision for the next decade.

J Proteomics. 2016 Sep 13;

Authors: Gadher SJ, Kovarova H

Abstract
The Central and Eastern European Proteomic Conference (CEEPC), has reached a special milestone as it celebrates its 10th anniversary. Today, an expansive network of proteomics in Central and Eastern Europe stands established to facilitate scientific interactions and collaborations in and around Central and Eastern Europe, as well as with international research institutions worldwide. Currently, when many conferences are struggling to attract participants, CEEPC is thriving in its status and stature as well as expanding by attracting newer member countries. CEEPC's success is driven by mutual respect between scientists sharing interest in proteomics and its applications in multidisciplinary research areas related to biological systems. This effort when interwoven with exciting ambience steeped with culture, and tradition is also a reason why participants enjoy it. CEEPC's careful balance between excellence and cohesion holds the key to its success. It is evident that CEEPC is ready for the next decade of excitement and expectations of multifaceted proteomics in Central and Eastern Europe. Additionally, in the era of emerging personalized medicine where treatment selection for each patient is becoming individualized, CEEPC and proteomics is expected to play a significant role moving forward for the benefit of mankind.

PMID: 27638426 [PubMed - as supplied by publisher]

A Liver-Centric Multiscale Modeling Framework for Xenobiotics.

PLoS One. 2016;11(9):e0162428

Authors: Sluka JP, Fu X, Swat M, Belmonte JM, Cosmanescu A, Clendenon SG, Wambaugh JF, Glazier JA

Abstract
We describe a multi-scale, liver-centric in silico modeling framework for acetaminophen pharmacology and metabolism. We focus on a computational model to characterize whole body uptake and clearance, liver transport and phase I and phase II metabolism. We do this by incorporating sub-models that span three scales; Physiologically Based Pharmacokinetic (PBPK) modeling of acetaminophen uptake and distribution at the whole body level, cell and blood flow modeling at the tissue/organ level and metabolism at the sub-cellular level. We have used standard modeling modalities at each of the three scales. In particular, we have used the Systems Biology Markup Language (SBML) to create both the whole-body and sub-cellular scales. Our modeling approach allows us to run the individual sub-models separately and allows us to easily exchange models at a particular scale without the need to extensively rework the sub-models at other scales. In addition, the use of SBML greatly facilitates the inclusion of biological annotations directly in the model code. The model was calibrated using human in vivo data for acetaminophen and its sulfate and glucuronate metabolites. We then carried out extensive parameter sensitivity studies including the pairwise interaction of parameters. We also simulated population variation of exposure and sensitivity to acetaminophen. Our modeling framework can be extended to the prediction of liver toxicity following acetaminophen overdose, or used as a general purpose pharmacokinetic model for xenobiotics.

PMID: 27636091 [PubMed - as supplied by publisher]

CardioTF, a database of deconstructing transcriptional circuits in the heart system.

PeerJ. 2016;4:e2339

Authors: Zhen Y

Abstract
BACKGROUND: Information on cardiovascular gene transcription is fragmented and far behind the present requirements of the systems biology field. To create a comprehensive source of data for cardiovascular gene regulation and to facilitate a deeper understanding of genomic data, the CardioTF database was constructed. The purpose of this database is to collate information on cardiovascular transcription factors (TFs), position weight matrices (PWMs), and enhancer sequences discovered using the ChIP-seq method.
METHODS: The Naïve-Bayes algorithm was used to classify literature and identify all PubMed abstracts on cardiovascular development. The natural language learning tool GNAT was then used to identify corresponding gene names embedded within these abstracts. Local Perl scripts were used to integrate and dump data from public databases into the MariaDB management system (MySQL). In-house R scripts were written to analyze and visualize the results.
RESULTS: Known cardiovascular TFs from humans and human homologs from fly, Ciona, zebrafish, frog, chicken, and mouse were identified and deposited in the database. PWMs from Jaspar, hPDI, and UniPROBE databases were deposited in the database and can be retrieved using their corresponding TF names. Gene enhancer regions from various sources of ChIP-seq data were deposited into the database and were able to be visualized by graphical output. Besides biocuration, mouse homologs of the 81 core cardiac TFs were selected using a Naïve-Bayes approach and then by intersecting four independent data sources: RNA profiling, expert annotation, PubMed abstracts and phenotype.
DISCUSSION: The CardioTF database can be used as a portal to construct transcriptional network of cardiac development.
AVAILABILITY AND IMPLEMENTATION: Database URL: http://www.cardiosignal.org/database/cardiotf.html.

PMID: 27635320 [PubMed]

Systems Biology - Opportunities and Challenges: The Application of Proteomics to Study the Cardiovascular Extracellular Matrix.

Cardiovasc Res. 2016 Sep 15;

Authors: Barallobre-Barreiro J, Lynch M, Yin X, Mayr M

Abstract
Systems biology approaches including proteomics are becoming more widely used in cardiovascular research. In this review article, we focus on the application of proteomics to the cardiac extracellular matrix. Extracellular matrix remodelling is a hallmark of many cardiovascular diseases. Proteomic techniques using mass spectrometry provide a platform for the comprehensive analysis of extracellular matrix proteins without a priori assumptions. Proteomics overcomes various constraints inherent to conventional antibody detection. On the other hand, studies that use whole tissue lysates for proteomic analysis mask the identification of the less abundant extracellular matrix constituents. In this review, we first discuss decellularization-based methods that enrich for extracellular matrix proteins in cardiac tissue, and how targeted mass spectrometry allows for accurate protein quantification. The second part of the review will focus on post-translational modifications including hydroxylation and glycosylation and on the release of matrix fragments with biological activity (matrikines), all of which can be interrogated by proteomic techniques.

PMID: 27635058 [PubMed - as supplied by publisher]

Systematic network assessment of the carcinogenic activities of cadmium.

Toxicol Appl Pharmacol. 2016 Sep 12;

Authors: Chen P, Duan X, Li M, Huang C, Li J, Chu R, Ying H, Song H, Jia X, Ba Q, Wang H

Abstract
Cadmium has been defined as type I carcinogen for humans, but the underlying mechanisms of its carcinogenic activity and its influence on protein-protein interactions in cells are not fully elucidated. The aim of the current study was to evaluate, systematically, the carcinogenic activity of cadmium with systems biology approaches. From a literature search of 209 studies that performed with cellular models, 208 proteins influenced by cadmium exposure were identified. All of these were assessed by Western blotting and were recognized as key nodes in network analyses. The protein-protein functional interaction networks were constructed with NetBox software and visualized with Cytoscape software. These cadmium-rewired genes were used to construct a scale-free, highly connected biological protein interaction network with 850 nodes and 8770 edges. Of the network, nine key modules were identified and 60 key signaling pathways, including the estrogen, RAS, PI3K-Akt, NF-kB, HIF-1α, Jak-STAT, and TGF-β signaling pathways, were significantly enriched. With breast cancer, colorectal and prostate cancer cellular models, we validated the key node genes in the network that had been previously reported or inferred form the network by Western blotting methods, including STAT3, JNK, p38, SMAD2/3, P65, AKT1, and HIF-1α. These results suggested the established network was robust and provided a systematic view of the carcinogenic activities of cadmium in human.

PMID: 27634459 [PubMed - as supplied by publisher]

Putting RNA to work: Translating RNA fundamentals into biotechnological engineering practice.

Biotechnol Adv. 2015 Dec;33(8):1829-44

Authors: Peters G, Coussement P, Maertens J, Lammertyn J, De Mey M

Abstract
Synthetic biology, in close concert with systems biology, is revolutionizing the field of metabolic engineering by providing novel tools and technologies to rationally, in a standardized way, reroute metabolism with a view to optimally converting renewable resources into a broad range of bio-products, bio-materials and bio-energy. Increasingly, these novel synthetic biology tools are exploiting the extensive programmable nature of RNA, vis-à-vis DNA- and protein-based devices, to rationally design standardized, composable, and orthogonal parts, which can be scaled and tuned promptly and at will. This review gives an extensive overview of the recently developed parts and tools for i) modulating gene expression ii) building genetic circuits iii) detecting molecules, iv) reporting cellular processes and v) building RNA nanostructures. These parts and tools are becoming necessary armamentarium for contemporary metabolic engineering. Furthermore, the design criteria, technological challenges, and recent metabolic engineering success stories of the use of RNA devices are highlighted. Finally, the future trends in transforming metabolism through RNA engineering are critically evaluated and summarized.

PMID: 26514597 [PubMed - indexed for MEDLINE]

Pyruvate production in Candida glabrata: manipulation and optimization of physiological function.

Crit Rev Biotechnol. 2016;36(1):1-10

Authors: Li S, Chen X, Liu L, Chen J

Abstract
Candida glabrata, a multi-vitamin auxotrophic yeast, can accumulate a large amount of pyruvate extracellularly using glucose as the carbon source, a characteristic that has facilitated the cost-effective biotechnological production of pyruvate on an industrial scale. In this review, we describe the current advances in further improving the performance of C. glabrata for efficient pyruvate production, which includes: optimization of the vitamin and dissolved oxygen concentrations, regulation of intracellular cofactor levels and improvement of the environmental robustness of C. glabrata. We also discuss the current efforts using systems biology to understand the metabolism of C. glabrata. Finally, perspectives on engineering and exploiting C. glabrata as a cell factory for efficiently producing various chemicals and materials are discussed.

PMID: 23883073 [PubMed - indexed for MEDLINE]

Systems Biology-Based Investigation of Cellular Antiviral Drug Targets Identified by Gene-Trap Insertional Mutagenesis.

PLoS Comput Biol. 2016 Sep;12(9):e1005074

Authors: Cheng F, Murray JL, Zhao J, Sheng J, Zhao Z, Rubin DH

Abstract
Viruses require host cellular factors for successful replication. A comprehensive systems-level investigation of the virus-host interactome is critical for understanding the roles of host factors with the end goal of discovering new druggable antiviral targets. Gene-trap insertional mutagenesis is a high-throughput forward genetics approach to randomly disrupt (trap) host genes and discover host genes that are essential for viral replication, but not for host cell survival. In this study, we used libraries of randomly mutagenized cells to discover cellular genes that are essential for the replication of 10 distinct cytotoxic mammalian viruses, 1 gram-negative bacterium, and 5 toxins. We herein reported 712 candidate cellular genes, characterizing distinct topological network and evolutionary signatures, and occupying central hubs in the human interactome. Cell cycle phase-specific network analysis showed that host cell cycle programs played critical roles during viral replication (e.g. MYC and TAF4 regulating G0/1 phase). Moreover, the viral perturbation of host cellular networks reflected disease etiology in that host genes (e.g. CTCF, RHOA, and CDKN1B) identified were frequently essential and significantly associated with Mendelian and orphan diseases, or somatic mutations in cancer. Computational drug repositioning framework via incorporating drug-gene signatures from the Connectivity Map into the virus-host interactome identified 110 putative druggable antiviral targets and prioritized several existing drugs (e.g. ajmaline) that may be potential for antiviral indication (e.g. anti-Ebola). In summary, this work provides a powerful methodology with a tight integration of gene-trap insertional mutagenesis testing and systems biology to identify new antiviral targets and drugs for the development of broadly acting and targeted clinical antiviral therapeutics.

PMID: 27632082 [PubMed - as supplied by publisher]

MicroRNAs as biomarkers and regulators of nonalcoholic fatty liver disease.

J Dig Dis. 2016 Sep 15;

Authors: Liu XL, Cao HX, Fan JG

Abstract
Nonalcoholic fatty liver disease (NAFLD) is a complicated disease affected by the interaction between environmental and genetic factors, and the precise pathogenesis of the disease is not fully understood. There is a need to better understand the pathogenesis of NAFLD and identify noninvasive diagnostic methods. Recent advances in systems biology and epigenetics have improved our understanding of the genotype-phenotype relationships present in NAFLD. MicroRNAs e important regulators of a wide range of biological processes, and they are protected from the RNAase in body fluids and are extremely stable, making them attractive candidate biomarkers for the early detection of disease and monitoring disease progression. In this review, we summarize the current knowledge on microRNAs as potential biomarkers of different stages of NAFLD and for the prognosis of advanced disease stages. Furthermore, we discuss the implications of microRNAs that have functions in lipid metabolism and hepatic steatosis as well as in hepatic inflammation and fibrosis with regard to the pathogenesis of NAFLD.

PMID: 27628945 [PubMed - as supplied by publisher]

Re: The "Omics" of Human Male Infertility: Integrating Big Data in a Systems Biology Approach.

J Urol. 2016 Oct;196(4):1230-1232

Authors: Niederberger C

PMID: 27628827 [PubMed - as supplied by publisher]