Integrative Systems Biology Research Articles

Factors that differentiate Traumatic Brain Injury (TBI) patients from Post‐Traumatic Stress Disorder (PTSD) patients among Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) veterans

Traumatic Brain Injury (TBI) has become the “signature wound” of Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF). Due to the increased use of improvised explosive devices by the insurgent forces and the unavoidable facial exposure of our combat troops, even when wearing protective gear, estimates suggest that as many as 20 % to 30 % of returning soldiers may eventually exhibit symptoms of TBI. Post‐Traumatic Stress Disorder (PTSD), as defined by the American Psychiatric Association, is a serious behavioral health disorder, and it has been estimated that 17.1 % of soldiers returning from Iraq, and 11.2 % of those returning from Afghanistan, have experienced major depression, generalized anxiety, and/or PTSD. As a part of the present effort, investigators within the Integrative Systems Biology Program (ISB), at US Army Center for Environmental Health Research (USACEHR), are working with collaborators from the Dwight D. Eisenhower Army Medical Center (DDEAMC) to screen for potential biomarkers associated with neuronal injury. In this pilot study, blood samples were collected at DDEAMC from patients diagnosed with PTSD, TBI, or both, and shared with USACEHR for multi‐omics analysis for identification of candidate genes/proteins distinguishing between TBI and PTSD. The candidate gene/protein approach is viewed as only a first step toward identifying molecular mechanisms that are likely to be involved in the physiologic consequences of TBI/PTSD. Gene expression, DNA methylation, and targeted proteomics analysis have been completed with these samples. Functional pathway predictions indicate possible overlaps of networks enriched by differentially expressed genes and methylated genes. The advancements realized through the current findings need to be validated using larger sample sizes, and it will be important to include a gender/age/ethnicity‐matched control. The results of this research will be leveraged in multiple ways to improve the health and treatment of returning soldiers diagnosed with TBI/PTSD.Support or Funding InformationDISCLAIMERS: Research was conducted in compliance with all Federal Requirements. The views expressed are those of the authors and do not constitute endorsement by the U.S. Army.

Epistemic Identities in Interdisciplinary Science

We introduce “epistemic identities” as a concept helpful for understanding the dynamics of interdisciplinary science practice. After acknowledging the ambiguity of “identity” and examining divergent meanings, we argue that analysis of identity is necessary in order to account for social and personal dimensions of practice non-reductively, and to better understand values and implicit hierarchies in science practice, as these, in turn, influence cognitive practices. With reference to ethnographic data from two integrative systems biology laboratories, we analyze specifically three theories of identity in terms of their affordances for understanding intergroup characterizations in interdisciplinary problem spaces.

Promise and peril in nanomedicine: the challenges and needs for integrated systems biology approaches to define health risk.

In the 1966s visionary film ‘Fantastic Voyage’ a submarine crew was shrunk to 100 nm in size and injected into the body of an injured scientist to repair his damaged brain. The movie (written by Harry Kleiner; directed by Richard Fleischer; novel by Isaac Asimov) drew attention to the potential power of engineered nanoscale structures and devices to construct, monitor, control, treat, and repair individual cells. Even more interesting was the fact that the film elegantly noted that the structure had to be miniaturized to a size that is not detected by the body's immune surveillance system, and highlighted the many physiological barriers that are encountered on the submarine's long journey to the target. Although the concept of miniaturizing humans remains an element of science fiction, targeted drug delivery through nanobots to treat diseases such as cancer is now a reality. The ability of nanobots to evade immune surveillance is one of the most attractive features of nanoscale materials that are exploited in the field of medicine for molecular diagnostics, targeted drug delivery, and therapy of diseases. This article will provide a concise opinion on the state‐of‐the‐art, the challenges, and the use of systems biology—another equally revolutionary field of science—to assess the unique health hazards of nanomaterial exposures. WIREs Nanomed Nanobiotechnol 2018, 10:e1465. doi: 10.1002/wnan.1465This article is categorized under: 1Therapeutic Approaches and Drug Discovery > Emerging Technologies2Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials

Integrated systems biology analysis of KSHV latent infection reveals viral induction and reliance on peroxisome mediated lipid metabolism.

Kaposi’s Sarcoma associated Herpesvirus (KSHV), an oncogenic, human gamma-herpesvirus, is the etiological agent of Kaposi’s Sarcoma the most common tumor of AIDS patients world-wide. KSHV is predominantly latent in the main KS tumor cell, the spindle cell, a cell of endothelial origin. KSHV modulates numerous host cell-signaling pathways to activate endothelial cells including major metabolic pathways involved in lipid metabolism. To identify the underlying cellular mechanisms of KSHV alteration of host signaling and endothelial cell activation, we identified changes in the host proteome, phosphoproteome and transcriptome landscape following KSHV infection of endothelial cells. A Steiner forest algorithm was used to integrate the global data sets and, together with transcriptome based predicted transcription factor activity, cellular networks altered by latent KSHV were predicted. Several interesting pathways were identified, including peroxisome biogenesis. To validate the predictions, we showed that KSHV latent infection increases the number of peroxisomes per cell. Additionally, proteins involved in peroxisomal lipid metabolism of very long chain fatty acids, including ABCD3 and ACOX1, are required for the survival of latently infected cells. In summary, novel cellular pathways altered during herpesvirus latency that could not be predicted by a single systems biology platform, were identified by integrated proteomics and transcriptomics data analysis and when correlated with our metabolomics data revealed that peroxisome lipid metabolism is essential for KSHV latent infection of endothelial cells.

Rationale and Design of Family-Based Approach in a Minority Community Integrating Systems–Biology for Promotion of Health (FAMILIA)

The 2020 American Heart Association Impact Goal aims to improve cardiovascular health of all Americans by 20% while reducing deaths from cardiovascular disease and stroke by 20%. A large step toward this goal would be to better understand and take advantage of the significant intersection between behavior and biology across the entire life-span. In the proposed FAMILIA studies, we aim to directly address this major knowledge and clinical health gap by implementing an integrated family-centric health promotion intervention and focusing on the intersection of environment and behavior, while understanding the genetic and biologic basis of cardiovascular disease. We plan to recruit 600 preschool children and their 600 parents or caregivers from 12-15 Head Start schools in Harlem, NY, and perform a 2:1 (2 intervention/1 control) cluster randomization of the schools. The preschool children will receive our intensive 37-hour educational program as the intervention for 4 months. For the adults, those in the "intervention" group will be randomly assigned to 1 of 2 intervention programs: an "individual-focused" or "peer-to-peer based." The primary outcome in children will be a composite score of knowledge (K), attitudes (A), habits (H), related to body mass index Z score (B), exercise (E), and alimentation (A) (KAH-BEA), using questionnaires and anthropometric measurements. For adults, the primary outcome will be a composite score for behaviors/outcomes related to blood pressure, exercise, weight, alimentation (diet) and tobacco (smoking; Fuster-BEWAT score). Saliva will be collected from the children for SNP genotyping, and blood will be collected from adults for RNA sequencing to identify network models and predictors of primary prevention outcomes. The FAMILIA studies seek to demonstrate that targeting a younger age group (3-5 years) and using a family-based approach may be a critical strategy in promoting cardiovascular health across the life-span.

Linking childhood allergic asthma phenotypes with endotype through integrated systems biology: current evidence and research needs.

Asthma and other complex diseases results from a complex web of interactions involving inflammation, immunity, cell cycle, apoptosis, and metabolic perturbations across multiple organ systems. The extent to which various degrees of the age at onset, symptom severity, and the natural progression of the disease reflect multiple disease subtypes, influenced by unique process of development remains unknown. One of the most critical challenges to our understanding stems from incomplete understanding of the mechanisms. Within this review, we focus on the phenotypes of childhood allergic asthma as the basis to better understand the endotype for quantitative define subtypes of asthma. We highlight some of the known mechanistic pathways associated with the key hallmark events before the asthma onset. In particular, we examine how the recent advent of multiaxial -omics technologies and systems biology could help to clarify our current understanding of the pathway. We review how a large volume of molecular, genomic data generated by multiaxial technologies could be digested to identify cogent pathophysiologic molecular networks. We highlight some recent successes in application of these technologies within the context of other disease conditions for therapeutic interventions. We conclude by summarizing the research needs for the predictive value of preclinical biomarkers.

HD Physiology Project\u2014Japanese efforts to promote multilevel integrative systems biology and physiome research

The HD Physiology Project is a Japanese research consortium that aimed to develop methods and a computational platform in which physiological and pathological information can be described in high-level definitions across multiple scales of time and size. During the 5 years of this project, an appropriate software platform for multilevel functional simulation was developed and a whole-heart model including pharmacokinetics for the assessment of the proarrhythmic risk of drugs was developed. In this article, we outline the description and scientific strategy of this project and present the achievements and influence on multilevel integrative systems biology and physiome research.

An Integrative Developmental Genomics and Systems Biology Approach to Identify an In Vivo Sox Trio-Mediated Gene Regulatory Network in Murine Embryos.

Embryogenesis is an intricate process involving multiple genes and pathways. Some of the key transcription factors controlling specific cell types are the Sox trio, namely, Sox5, Sox6, and Sox9, which play crucial roles in organogenesis working in a concerted manner. Much however still needs to be learned about their combinatorial roles during this process. A developmental genomics and systems biology approach offers to complement the reductionist methodology of current developmental biology and provide a more comprehensive and integrated view of the interrelationships of complex regulatory networks that occur during organogenesis. By combining cell type-specific transcriptome analysis and in vivo ChIP-Seq of the Sox trio using mouse embryos, we provide evidence for the direct control of Sox5 and Sox6 by the transcriptional trio in the murine model and by Morpholino knockdown in zebrafish and demonstrate the novel role of Tgfb2, Fbxl18, and Tle3 in formation of Sox5, Sox6, and Sox9 dependent tissues. Concurrently, a complete embryonic gene regulatory network has been generated, identifying a wide repertoire of genes involved and controlled by the Sox trio in the intricate process of normal embryogenesis.

Application of integrative genomics and systems biology to conventional and in vitro reproductive traits in cattle

Application of integrative genomics and systems biology to conventional and in vitro reproductive traits in cattle

Systems biology of resilience and optimal health: integrating Chinese and Western medicine perspectives

Western science has been strong in measuring details of biological systems such as gene expression levels and metabolite concentrations, and has generally followed a bottom up approach with regard to explaining biological phenomena. Chinese medicine in contrast has evolved as a top down approach in which body and mind is seen as a whole, a phenomenological approach based on the organization and dynamics of symptom patterns. Western and Chinese perspectives are developing towards a ‘middle out’ approach. Chinese medicine diagnosis, we will argue, allows bridging the gap between biologists and psychologists and offers new opportunities for the development of health monitoring tools and health promotion strategies. In this paper, health, resilience and stress concepts are explored from an integrated systems biology perspective. This is followed by a discussion about measuring aspects of health and resilience. Then the issue of how to integrate different types of data is discussed. Semi-quantitative modeling appears to be very suitable and looks promising for building integrated health models. The challenge for the future lies in applying those models in developing personalized health monitoring and advice systems that will tempt people to lead more healthy lives.

Graph Theory-Based Analysis of the Lymph Node Fibroblastic Reticular Cell Network.

Secondary lymphoid organs have developed segregated niches that are able to initiate and maintain effective immune responses. Such global organization requires tight control of diverse cellular components, specifically those that regulate lymphocyte trafficking. Fibroblastic reticular cells (FRCs) form a densely interconnected network in lymph nodes and provide key factors necessary for T cell migration and retention, and foster subsequent interactions between T cells and dendritic cells. Development of integrative systems biology approaches has made it possible to elucidate this multilevel complexity of the immune system. Here, we present a graph theory-based analysis of the FRC network in murine lymph nodes, where generation of the network topology is performed using high-resolution confocal microscopy and 3D reconstruction. This approach facilitates the analysis of physical cell-to-cell connectivity, and estimation of topological robustness and global behavior of the network when it is subjected to perturbation in silico.

Agent-based re-engineering of ErbB signaling: a modeling pipeline for integrative systemsbiology.

Experiments in systems biology are generally supported by a computational model which quantitatively estimates the parameters of the system by finding the best fit to the experiment. Mathematical models have proved to be successful in reverse engineering the system. The data generated is interpreted to understand the dynamics of the underlying phenomena. The question we have sought to answer is that - is it possible to use an agent-based approach to re-engineer a biological process, making use of the available knowledge from experimental and modelling efforts? Can the bottom-up approach benefit from the top-down exercise so as to create an integrated modelling formalism for systems biology? We propose a modelling pipeline that learns from the data given by reverse engineering, and uses it for re-engineering the system, to carry out in-silico experiments. A mathematical model that quantitatively predicts co-expression of EGFR-HER2 receptors in activation and trafficking has been taken for this study. The pipeline architecture takes cues from the population model that gives the rates of biochemical reactions, to formulate knowledge-based rules for the particle model. Agent-based simulations using these rules, support the existing facts on EGFR-HER2 dynamics. We conclude that, re-engineering models, built using the results of reverse engineering, opens up the possibility of harnessing the power pack of data which now lies scattered in literature. Virtual experiments could then become more realistic when empowered with the findings of empirical cell biology and modelling studies. Implemented on the Agent Modelling Framework developed in-house. C ++ code templates available in Supplementary material . liz.csir@gmail.com. Supplementary data are available at Bioinformatics online.

Partial exhaustion of CD8 T cells and clinical response to teplizumab in new-onset type 1 diabetes.

Biologic treatment of T1D typically results in transient stabilization of C-peptide levels (a surrogate for endogenous insulin secretion) in some patients, followed by progression at the same rate as in untreated control groups. Here, we used integrated systems biology and flow cytometry approaches with clinical trial blood samples to elucidate pathways associated with C-peptide stabilization in T1D subjects treated with the anti-CD3 monoclonal antibody teplizumab. We identified a population of CD8 T cells that accumulated in subjects with the best response to treatment (responders) and showed that these cells phenotypically resembled exhausted T cells by expressing high levels of the transcription factor EOMES, effector molecules, and multiple inhibitory receptors (IRs), including TIGIT and KLRG1. These cells expanded after treatment, with levels peaking after 3-6 months. To functionally characterize these exhausted-like T cells, we isolated memory CD8 TIGIT+KLRG1+ T cells from responders and showed that they exhibited expanded TCR clonotypes, indicative of prior in vivo expansion; recognized a broad-based spectrum expressed of environmental and auto-antigens; and were hypo-proliferative during polyclonal stimulation, increasing expression of IR genes and decreasing cell cycle genes. Triggering these cells with a recombinant ligand for TIGIT during polyclonal stimulation further downregulated their activation, demonstrating their exhausted phenotype was not terminal. These findings identify and functionally characterize a partially exhausted cell type associated with response to teplizumab therapy and suggest that pathways regulating T cell exhaustion may play a role in successful immune interventions for T1D.

Integrative Systems Biology Investigation of Fabry Disease

Fabry disease (FD) is a rare X-linked recessive genetic disorder caused by a deficient activity of the lysosomal enzyme alpha-galactosidase A (GLA) and is characterised by intra-lysosomal accumulation of globotriaosylceramide (Gb3). We performed a meta-analysis of peer-reviewed publications including high-throughput omics technologies including naïve patients and those undergoing enzyme replacement therapy (ERT). This study describes FD on a systems level using a systems biology approach, in which molecular data sourced from multi-omics studies is extracted from the literature and integrated as a whole in order to reveal the biochemical processes and molecular pathways potentially affected by the dysregulation of differentially expressed molecules. In this way new insights are provided that describe the pathophysiology of this rare disease. Using gene ontology and pathway term clustering, FD displays the involvement of major biological processes such as the acute inflammatory response, regulation of wound healing, extracellular matrix (ECM) remodelling, regulation of peptidase activity, and cellular response to reactive oxygen species (ROS). Differential expression of acute-phase response proteins in the groups of naïve (up-regulation of ORM1, ORM2, ITIH4, SERPINA3 and FGA) and ERT (down-regulation of FGA, ORM1 and ORM2) patients could be potential hallmarks for distinction of these two patient groups.

A systems biology approach reveals major metabolic changes in the thermoacidophilic archaeon Sulfolobus solfataricus in response to the carbon source L-fucose versus D-glucose.

Archaea are characterised by a complex metabolism with many unique enzymes that differ from their bacterial and eukaryotic counterparts. The thermoacidophilic archaeon Sulfolobus solfataricus is known for its metabolic versatility and is able to utilize a great variety of different carbon sources. However, the underlying degradation pathways and their regulation are often unknown. In this work, the growth on different carbon sources was analysed, using an integrated systems biology approach. The comparison of growth on L-fucose and D-glucose allows first insights into the genome-wide changes in response to the two carbon sources and revealed a new pathway for L-fucose degradation in S. solfataricus. During growth on L-fucose major changes in the central carbon metabolic network, as well as an increased activity of the glyoxylate bypass and the 3-hydroxypropionate/4-hydroxybutyrate cycle were observed. Within the newly discovered pathway for L-fucose degradation the following key reactions were identified: (i) L-fucose oxidation to L-fuconate via a dehydrogenase, (ii) dehydration to 2-keto-3-deoxy-L-fuconate via dehydratase, (iii) 2-keto-3-deoxy-L-fuconate cleavage to pyruvate and L-lactaldehyde via aldolase and (iv) L-lactaldehyde conversion to L-lactate via aldehyde dehydrogenase. This pathway as well as L-fucose transport shows interesting overlaps to the D-arabinose pathway, representing another example for pathway promiscuity in Sulfolobus species.

Human environmental disease network: A computational model to assess toxicology of contaminants

During the past decades, many epidemiological, toxicological and biological studies have been performed to assess the role of environmental chemicals as potential toxicants associated with diverse human disorders. However, the relationships between diseases based on chemical exposure rarely have been studied by computational biology. We developed a human environmental disease network (EDN) to explore and suggest novel disease-disease and chemical-disease relationships. The presented scored EDN model is built upon the integration of systems biology and chemical toxicology using information on chemical contaminants and their disease relationships reported in the TDDB database. The resulting human EDN takes into consideration the level of evidence of the toxicant-disease relationships, allowing inclusion of some degrees of significance in the disease-disease associations. Such a network can be used to identify uncharacterized connections between diseases. Examples are discussed for type 2 diabetes (T2D). Additionally, this computational model allows confirmation of already known links between chemicals and diseases (e.g., between bisphenol A and behavioral disorders) and also reveals unexpected associations between chemicals and diseases (e.g., between chlordane and olfactory alteration), thus predicting which chemicals may be risk factors to human health. The proposed human EDN model allows exploration of common biological mechanisms of diseases associated with chemical exposure, helping us to gain insight into disease etiology and comorbidity. This computational approach is an alternative to animal testing supporting the 3R concept.

Systems biology integration of proteomic data in rodent models of depression reveals involvement of the immune response and glutamatergic signaling.

The pathophysiological basis of major depression is incompletely understood. Recently, numerous proteomic studies have been performed in rodent models of depression to investigate the molecular underpinnings of depressive-like behaviours with an unbiased approach. The objective of the study is to integrate the results of these proteomic studies in depression models to shed light on the most relevant molecular pathways involved in the disease. Network analysis is performed integrating preexisting proteomic data from rodent models of depression. The IntAct mouse and the HRPD are used as reference protein-protein interaction databases. The functionality analyses of the networks are then performed by testing overrepresented GO biological process terms and pathways. Functional enrichment analyses of the networks revealed an association with molecular processes related to depression in humans, such as those involved in the immune response. Pathways impacted by clinically effective antidepressants are modulated, including glutamatergic signaling and neurotrophic responses. Moreover, dysregulations of proteins regulating energy metabolism and circadian rhythms are implicated. The comparison with protein pathways modulated in depressive patients revealed significant overlapping. This systems biology study supports the notion that animal models can contribute to the research into the biology and therapeutics of depression.

Development of an integrated system biology model for predicting mixtures of chemicals: The case of the azole fungicides

Development of an integrated system biology model for predicting mixtures of chemicals: The case of the azole fungicides

Integrative systems biology approach to identify novel glucocorticoid-based biomarkers and treatment targets for PTSD

The objective of this study was to investigate the effect of dietary supplementation of pioglitazone (PGT), a specific ligand for PPARγ, on metabolic dynamics, milk production, and reproductive performance of transition dairy cows. Eighty multiparous Holstein cows in their second or more lactations were blocked by the calving date and parity and assigned randomly to four dietary groups (n = 20 cow/treatment) including control (no PGT−/−), supplemented with PGT (6-mg PGT/kg body weight) from Day −14 to +21 relative to parturition (PGT+/+) or only during prepartum (PGT+/−) or postpartum periods (PGT−/+). Postpartum body condition score and body weight loss decreased (P < 0.05) in all PGT-supplemented groups. Milk yield was not affected by PGT supplementation (P > 0.05). Percentage of milk fat decreased (P < 0.05) in all PGT-treated groups; however, milk fat yield was lower (P < 0.05) in PGT (+/+) and PGT (+/−) groups compared with PGT (−/−). Peripartum (Day −7 to +7) concentrations of plasma nonesterified fatty acids and β-Hydroxybutyrate decreased in PGT (+/+) but not in the PGT (−/−) group (P < 0.05). During the postpartum period, PGT reduced (P > 0.05) plasma concentrations of nonesterified fatty acids in all PGT-treated groups but did not affect β-Hydroxybutyrate level. Plasma concentrations of triglycerides decreased in all PGT-supplemented groups. Supplementation of PGT increased the peripartum concentrations of plasma glucose in PGT (+/+) and PGT (+/−) groups compared with control. Plasma concentrations of insulin-like growth factor 1 were higher in PGT (+/+) compared with the control group during both the peripartum and postpartum periods. Plasma concentrations of growth hormone and insulin were not affected by PGT treatment (P > 0.05). Mean days to ovulation were lower in PGT (+/+) and PGT (-/+), and the proportion of cows ovulating by Day 14 postpartum was higher in PGT (+/+) compared with control. Days open were shorter in PGT (+/+), PGT (+/−), and PGT (−/+) groups compared with control. However, the proportion of pregnant cows at 120 days in milk were higher in all PGT-supplemented groups. The results showed positive effects of dietary supplementation of PGT, especially supplementation during both the prepartum and postpartum periods, on metabolic dynamics, ovarian function, and reproductive performance in transition dairy cows.

The gain and loss of long noncoding RNA associated-competing endogenous RNAs in prostate cancer.

Prostate cancer (PC) is one of the most common solid tumors in men. However, the molecular mechanism of PC remains unclear. Numerous studies have demonstrated that long noncoding RNA (lncRNA) can act as microRNA (miRNA) sponge, one type of competing endogenous RNAs (ceRNAs), which offers a novel viewpoint to elucidate the mechanisms of PC. Here, we proposed an integrative systems biology approach to infer the gain and loss of ceRNAs in PC. First, we re-annotated exon microarray data to obtain lncRNA expression profiles of PC. Second, by integrating mRNA and miRNA expression, as well as miRNA targets, we constructed lncRNA-miRNA-mRNA ceRNA networks in cancer and normal samples. The lncRNAs in these two ceRNA networks tended to have a longer transcript length and cover more exons than the lncRNAs not involved in ceRNA networks. Next, we further extracted the gain and loss ceRNA networks in PC. We found that the gain ceRNAs in PC participated in cell cycle, and the loss ceRNAs in PC were associated with metabolism. We also identified potential prognostic ceRNA pairs such as MALAT1-EGR2 and MEG3-AQP3. Finally, we inferred a novel mechanism of known drugs, such as cisplatin, for the treatment of PC through gain and loss ceRNA networks. The potential drugs such as 1,2,6-tri-O-galloyl-beta-D-glucopyranose (TGGP) could modulate lncRNA-mRNA competing relationships, which may uncover new strategy for treating PC. In summary, we systematically investigated the gain and loss of ceRNAs in PC, which may prove useful for identifying potential biomarkers and therapeutics for PC.