Systems Biology Research Papers - Academia.edu (original) (raw)

We report the construction of a genome-wide fish metabolic network model, MetaFishNet, and its application to analyzing high throughput gene expression data. This model is a stepping stone to broader applications of fish systems biology,... more

We report the construction of a genome-wide fish metabolic network model, MetaFishNet, and its application to analyzing high throughput gene expression data. This model is a stepping stone to broader applications of fish systems biology, for example by guiding study design through comparison with human metabolism and the integration of multiple data types. MetaFishNet resources, including a pathway enrichment analysis tool, are accessible at http://metafishnet.appspot.com.

Background: Cells interact with their environment and they have to react adequately to internal and external changes such changes in nutrient composition, physical properties like temperature or osmolarity and other stresses. More... more

Background: Cells interact with their environment and they have to react adequately to internal and external changes such changes in nutrient composition, physical properties like temperature or osmolarity and other stresses. More specifically, they must be able to evaluate whether the external change is significant or just in the range of noise. Based on multiple external parameters they have to compute an optimal response. Cellular signaling pathways are considered as the major means of information perception and transmission in cells. Scope of Review: Here, we review different attempts to quantify information processing on the level of individual cells. We refer to Shannon entropy, mutual information, and informal measures of signaling pathway cross-talk and specificity. Major Conclusions: Information theory in systems biology has been successfully applied to identification of optimal pathway structures, mutual information and entropy as system response in sensitivity analysis, and quantification of input and output information. General Significance: While the study of information transmission within the framework of information theory in technical systems is an advanced field with high impact in engineering and telecommunication, its application to biological objects and processes is still restricted to specific fields such as neuroscience, structural and molecular biology. However, in systems biology dealing with a holistic understanding of biochemical systems and cellular signaling only recently a number of examples for the application of information theory have emerged. This article is part of a Special Issue entitled Systems Biology of Microorganisms.

Unlike traditional biological research that focuses on a small set of components, systems biology studies the complex interactions among a large number of genes, proteins, and other elements of biological networks and systems.... more

Unlike traditional biological research that focuses on a small set of components, systems biology studies the complex interactions among a large number of genes, proteins, and other elements of biological networks and systems. Host-pathogen systems biology examines the interactions between the components of two distinct organisms: a microbial or viral pathogen and its animal host. With the availability of complete genomic sequences of a variety of hosts and pathogens, together with breakthroughs in proteomics, metabolomics, and other experimental areas, the investigation of host-pathogen systems on a multitude of levels of detail has come within reach. This chapter introduces methods and approaches for the analysis of host-pathogen systems. We will particularly emphasize the role of biochemical networks for the study of complex relationships across species boundaries. Although the research area of host-pathogen systems biology spans multiple spatial and temporal scales, we will focus on the molecular and cellular aspects of pathogen-host interactions. We will cover the construction of biochemical networks, the identification of functional response sub-networks, and their comparative network analysis. These methods find application in the identification of host markers and drug targets for further drug development and therapeutic interventions. We will also provide a brief review of other modeling techniques and applications within host-pathogen systems biology, including rule-based modeling of signal transduction pathways, immune system models, and physiological top-down approaches.

The antimicrobial peptide human α-defensin 5 (HD5) is expressed in Paneth cells, secretory epithelial cells in the small intestine. Unlike other characterized defensins, HD5 is stored in secretory vesicles as a propeptide. The storage... more

The antimicrobial peptide human α-defensin 5 (HD5) is expressed in Paneth cells, secretory epithelial cells in the small intestine. Unlike other characterized defensins, HD5 is stored in secretory vesicles as a propeptide. The storage quantities of HD5 are ∼90-450 µg per cm 2 of mucosal surface area, which is sufficient to generate microbicidal concentrations in the intestinal lumen. HD5 peptides isolated from the intestinal lumen are proteolytically processed forms-HD5(56-94) and HD5(63-94)-that are cleaved at the Arg 55 -Ala 56 and Arg 62 -Thr 63 sites, respectively.We show here that a specific pattern of trypsin isozymes is expressed in Paneth cells, that trypsin colocalizes with HD5 and that this protease can efficiently cleave HD5 propeptide to forms identical to those isolated in vivo. By acting as a prodefensin convertase in human Paneth cells, trypsin is involved in the regulation of innate immunity in the small intestine.

Motivation: To promote a systems biology approach to understanding the biological effects of environmental stressors, the Chemical Effects in Biological Systems (CEBS) knowledge base is being developed to house data from multiple complex... more

Motivation: To promote a systems biology approach to understanding the biological effects of environmental stressors, the Chemical Effects in Biological Systems (CEBS) knowledge base is being developed to house data from multiple complex data streams in a systems friendly manner that will accommodate extensive querying from users. Unified data representation via a single object model will greatly aid in integrating data storage and management, and facilitate reuse of software to analyze and display data resulting from diverse differential expression or differential profile technologies. Data streams include, but are not limited to, gene expression analysis (transcriptomics), protein expression and protein-protein interaction analysis (proteomics) and changes in low molecular weight metabolite levels (metabolomics). Results: To enable the integration of microarray gene expression, proteomics and metabolomics data in the CEBS system, we designed an object model, Systems Biology Object Model (SysBio-OM). The model is comprehensive and leverages other open source efforts, namely the Micro-Array Gene Expression Object Model (MAGE-OM) and the Proteomics Experiment Data Repository (PEDRo) object model. SysBio-OM is designed by extending MAGE-OM to represent protein expression data elements (including those from PEDRo), protein-protein interaction and metabolomics data. SysBio-OM promotes the standardization of data representation and data quality by facilitating the capture of the minimum annotation required for an experiment. Such standardization refines the accuracy of data mining and interpretation. The * To whom correspondence should be addressed. † The authors wish it to be known that, in their opinion, these two authors should be regarded as joint First Authors. open source SysBio-OM model, which can be implemented on varied computing platforms is presented here. Availability: A universal modeling language depiction of the entire SysBio-OM is available at http://cebs.niehs.nih.gov/ SysBioOM/. The Rational Rose object model package is distributed under an open source license that permits unrestricted academic and commercial use and is available at http://cebs.niehs.nih.gov/cebsdownloads. The database and interface are being built to implement the model and will be available for public use at http://cebs.niehs.nih.gov.

Inflammation is a complex, multi-scale biologic response to stress that is also required for repair and regeneration after injury. Despite the repository of detailed data about the cellular and molecular processes involved in... more

Inflammation is a complex, multi-scale biologic response to stress that is also required for repair and regeneration after injury. Despite the repository of detailed data about the cellular and molecular processes involved in inflammation, including some understanding of its ...

We have various kinds of networks around us ranging from computer networks to social networks, food web, disease transmission networks and terrorist networks. Today, the concept and the reality of networks are playing an important role in... more

We have various kinds of networks around us ranging from computer networks to social networks, food web, disease
transmission networks and terrorist networks. Today, the concept and the reality of networks are playing an important role in modern society. From the last several years, scientists from different fields: including computer science, mathematics, physics, chemistry, sociology, and of course biology, deals with some kind of network and more recently coined a new terminology “network science”. In this article, biological networks are discussed with special focus on understanding
complex molecular interactions for better insight about a disease and how biological networks help in the development of future medicines.

Adverse outcome pathways (AOPs) are a recent toxicological construct that connects, in a formalized, transparent and quality-controlled way, mechanistic information to apical endpoints for regulatory purposes. AOP links a molecular... more

Adverse outcome pathways (AOPs) are a recent toxicological construct that connects, in a formalized, transparent and quality-controlled way, mechanistic information to apical endpoints for regulatory purposes. AOP links a molecular initiating event (MIE) to the adverse outcome (AO) via key events (KE), in a way specified by key event relationships (KER). Although this approach to formalize mechanistic toxicological information only started in 2010, over 200 AOPs have already been established. At this stage, new requirements arise, such as the need for harmonization and re-assessment, for continuous updating, as well as for alerting about pitfalls, misuses and limits of applicability. In this review, the history of the AOP concept and its most prominent strengths are discussed, including the advantages of a formalized approach, the systematic collection of weight of evidence, the linkage of mechanisms to apical end points, the examination of the plausibility of epidemiological data, ...

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Tocochromanols are recognized for nutritional content, plant stress response, and seed longevity. Here we present a systems biological approach to characterize and develop predictive assays for genes affecting tocochromanol variation in... more

Tocochromanols are recognized for nutritional content, plant stress response, and seed longevity. Here we present a systems biological approach to characterize and develop predictive assays for genes affecting tocochromanol variation in barley. Major QTL, detected in three regions of a SNP linkage map, affected multiple tocochromanol forms. Candidate genes were identified through barley/rice orthology and sequenced in genotypes with disparate tocochromanol profiles. Gene-specific markers, designed based on observed polymorphism, mapped to the originating QTL, increasing R2 values at the respective loci. Polymorphism within promoter regions corresponded to motifs known to influence gene expression. Quantitative PCR analysis revealed a trend of increased expression in tissues grown at cold temperatures. These results demonstrate utility of a novel method for rapid gene identification and characterization, and provide a resource for efficient development of barley lines with improved t...

With the advent of high-throughput biology, we now routinely scan cells and organisms at practically all levels, from genome to protein, metabolism, signaling and other cellular functions. This methodology allowed biological studies to... more

With the advent of high-throughput biology, we now routinely scan cells and organisms at practically all levels, from genome to protein, metabolism, signaling and other cellular functions. This methodology allowed biological studies to move from a reductionist approach, such as isolation of specific pathways and mechanisms, to a more integrative approach, where biological systems are seen as a network of interconnected components that provide specific outputs and functions in response to stimuli. Recent literature on biological networks demonstrates two important concepts that we will consider in this review: (i) cellular pathways are highly interconnected and should not be studied separately, but as a network; (ii) simple, recurrent feedback motifs within the network can produce very specific functions that favor their modular use. The first theme differs from the traditional approach in biology because it provides a framework (i.e., the network view) in which large datasets are analyzed with an unbiased view. The second theme (feedback motifs) shows the importance of locally analyzing the dynamic properties of biological networks in order to better understand their functionality. We will review these themes with examples from cell signaling networks, gene regulatory networks and metabolic pathways. The deregulation of cellular networks (metabolism, signaling etc.) is involved in cancer, but the size of the networks and resulting non-linear behavior do not allow for intuitive reasoning. In that context, we argue that the qualitative classification of the 'building blocs' of biological networks (i.e. the motifs) in terms of dynamics and functionality will be critical to improve our understanding of cancer biology and rationalize the wealth of information from high-throughput experiments. From the examples highlighted in this review, it is clear that dynamic feedback motifs can be used to provide a unified view of various cellular processes involved in cancer and this will be critical for future research on personalized and predictive cancer therapies.

Synthetic biology is an emerging field that strives to build increasingly complex biological networks through the integration of molecular biology and engineering. The growth of the field has been supported by progress in the design and... more

Synthetic biology is an emerging field that strives to build increasingly complex biological networks through the integration of molecular biology and engineering. The growth of the field has been supported by progress in the design and construction of synthetic genetic and protein networks. This has led to the possibility of assembling modular components to attain novel biological functions and tools. In addition, these synthetic networks give rise to insights that facilitate the investigation of interactions and phenomena in naturally-occurring networks. Integration of well-characterized biological components into higher order networks requires computational modeling approaches to rationally construct systems that are directed towards a desired outcome. A computational approach would improve the predictability of the underlying mechanisms that would otherwise be difficult to deduce through experimentation alone. The analysis and interpretation of both qualitative and quantitative ...

Elucidating the signalling mechanisms by which obesity leads to impaired insulin action is critical in the development of therapeutic strategies for the treatment of diabetes 1 . Recently, mice deficient for S6 Kinase 1 (S6K1), an... more

Elucidating the signalling mechanisms by which obesity leads to impaired insulin action is critical in the development of therapeutic strategies for the treatment of diabetes 1 . Recently, mice deficient for S6 Kinase 1 (S6K1), an effector of the mammalian target of rapamycin (mTOR) that acts to integrate nutrient and insulin signals 2 , were shown to be hypoinsulinaemic, glucose intolerant and have reduced b-cell mass 3 . However, S6K1deficient mice maintain normal glucose levels during fasting, suggesting hypersensitivity to insulin 3 , raising the question of their metabolic fate as a function of age and diet. Here, we report that S6K1-deficient mice are protected against obesity owing to enhanced b-oxidation. However on a high fat diet, levels of glucose and free fatty acids still rise in S6K1-deficient mice, resulting in insulin receptor desensitization. Nevertheless, S6K1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from S6K1 to insulin receptor substrate 1 (IRS1), which blunts S307 and S636/S639 phosphorylation; sites involved in insulin resistance 4,5 . Moreover, wild-type mice on a high fat diet as well as K/K A y and ob/ob (also known as Lep/Lep) mice-two genetic models of obesity-have markedly elevated S6K1 activity and, unlike S6K1-deficient mice, increased phosphorylation of IRS1 S307 and S636/S639. Thus under conditions of nutrient satiation S6K1 negatively regulates insulin signalling.

Complex networks theory offers a unique chance to describe protein structures at the light of the intra-molecular interactions network. The perspective is appealing, supported by evidences of the topology weight on protein function and... more

Complex networks theory offers a unique chance to describe protein structures at the light of the intra-molecular interactions network. The perspective is appealing, supported by evidences of the topology weight on protein function and structures.

The CD1 family is a large cluster of non-polymorphic, major histocompatibility complex (MHC) class-I-like molecules that bind distinct lipid-based antigens that are recognized by T cells. The most studied group of T cells that interact... more

The CD1 family is a large cluster of non-polymorphic, major histocompatibility complex (MHC) class-I-like molecules that bind distinct lipid-based antigens that are recognized by T cells. The most studied group of T cells that interact with lipid antigens are natural killer T (NKT) cells, which characteristically express a semi-invariant T-cell receptor (NKT TCR) that specifically recognizes the CD1 family member, CD1d. NKT-cell-mediated recognition of the CD1d-antigen complex has been implicated in microbial immunity, tumour immunity, autoimmunity and allergy. Here we describe the structure of a human NKT TCR in complex with CD1d bound to the potent NKT-cell agonist a-galactosylceramide, the archetypal CD1d-restricted glycolipid. In contrast to T-cell receptor-peptide-antigen-MHC complexes, the NKT TCR docked parallel to, and at the extreme end of the CD1d-binding cleft, which enables a lock-and-key type interaction with the lipid antigen. The structure provides a basis for the interaction between the highly conserved NKT TCR a-chain and the CD1d-antigen complex that is typified in innate immunity, and also indicates how variability of the NKT TCR b-chain can impact on recognition of other CD1d-antigen complexes. These findings provide direct insight into how a T-cell receptor recognizes a lipid-antigen-presenting molecule of the immune system.

Incomplete knowledge of biochemical pathways makes the holistic description of plant metabolism a non-trivial undertaking. Sensitive analytical platforms, which are capable of accurately quantifying the levels of the various molecular... more

Incomplete knowledge of biochemical pathways makes the holistic description of plant metabolism a non-trivial undertaking. Sensitive analytical platforms, which are capable of accurately quantifying the levels of the various molecular entities of the cell, can assist in tackling this task. However, the ever-increasing amount of highthroughput data, often from multiple technologies, requires significant computational efforts for integrative analysis. Here we introduce the application of network analysis to study plant metabolism and describe the construction and analysis of correlation-based networks from (time-resolved) metabolomics data. By investigating the interactions between metabolites, network analysis can help to interpret complex datasets through the identification of key network components. The relationship between structural and biological roles of network components can be evaluated and employed to aid metabolic engineering.

A systems biology approach was applied to investigate the mechanisms of chromosomal instability in melanoma cell lines. Chromosomal instability was quantified using array comparative genomic hybridization to identify somatic copy number... more

A systems biology approach was applied to investigate the mechanisms of chromosomal instability in melanoma cell lines. Chromosomal instability was quantified using array comparative genomic hybridization to identify somatic copy number alterations (deletions and duplications). Primary human melanocytes displayed an average of 8.5 alterations per cell primarily representing known polymorphisms. Melanoma cell lines displayed 25 to 131 alterations per cell, with an average of 68, indicative of chromosomal instability. Copy number alterations included approximately equal numbers of deletions and duplications with greater numbers of hemizygous (−1,+1) alterations than homozygous (−2,+2). Melanoma oncogenes, such as BRAF and MITF, and tumor suppressor genes, such as CDKN2A/B and PTEN, were included in these alterations. Duplications and deletions were functional as there were significant correlations between DNA copy number and mRNA expression for these genes. Spectral karyotype analysis of three lines confirmed extensive chromosomal instability with polyploidy, aneuploidy, deletions, duplications and chromosome rearrangements. Bioinformatic analysis identified a signature of gene expression that was correlated with chromosomal instability but this signature provided no clues to the mechanisms of instability. The signature failed to generate a significant (P=0.105) prediction of melanoma progression in a separate dataset. Chromosomal instability was not correlated with elements of DNA damage response such as radiosensitivity, nucleotide excision repair, expression of the DNA damage response biomarkers γH2AX and P-CHEK2, nor G1 or G2 checkpoint function. Chromosomal instability in melanoma cell lines appears to influence gene function but it is not simply explained by alterations in the system of DNA damage response.

Engulfment and subsequent degradation of apoptotic cells is an essential step that occurs throughout life in all multicellular organisms 1-3 . ELMO/Dock180/Rac proteins are a conserved signalling module for promoting the internalization... more

Engulfment and subsequent degradation of apoptotic cells is an essential step that occurs throughout life in all multicellular organisms 1-3 . ELMO/Dock180/Rac proteins are a conserved signalling module for promoting the internalization of apoptotic cell corpses 4,5 ; ELMO and Dock180 function together as a guanine nucleotide exchange factor (GEF) for the small GTPase Rac, and thereby regulate the phagocyte actin cytoskeleton during engulfment 4-6 . However, the receptor(s) upstream of the ELMO/ Dock180/Rac module are still unknown. Here we identify brainspecific angiogenesis inhibitor 1 (BAI1) as a receptor upstream of ELMO and as a receptor that can bind phosphatidylserine on apoptotic cells. BAI1 is a seven-transmembrane protein belonging to the adhesion-type G-protein-coupled receptor family, with an extended extracellular region 7-9 and no known ligands. We show that BAI1 functions as an engulfment receptor in both the recognition and subsequent internalization of apoptotic cells. Through multiple lines of investigation, we identify phosphatidylserine, a key 'eat-me' signal exposed on apoptotic cells 10-13 , as a ligand for BAI1. The thrombospondin type 1 repeats within the extracellular region of BAI1 mediate direct binding to phosphatidylserine. As with intracellular signalling, BAI1 forms a trimeric complex with ELMO and Dock180, and functional studies suggest that BAI1 cooperates with ELMO/Dock180/Rac to promote maximal engulfment of apoptotic cells. Last, decreased BAI1 expression or interference with BAI1 function inhibits the engulfment of apoptotic targets ex vivo and in vivo. Thus, BAI1 is a phosphatidylserine recognition receptor that can directly recruit a Rac-GEF complex to mediate the uptake of apoptotic cells.

8 typically slower than ϳ1 km s −1 ) might differ significantly from what is assumed by current modelling efforts 27 . The expected equation-of-state differences among small bodies (ice versus rock, for instance) presents another... more

8 typically slower than ϳ1 km s −1 ) might differ significantly from what is assumed by current modelling efforts 27 . The expected equation-of-state differences among small bodies (ice versus rock, for instance) presents another dimension of study; having recently adapted our code for massively parallel architectures (K. M. Olson and E.A, manuscript in preparation), we are now ready to perform a more comprehensive analysis.

by in situ X-ray observations based on the same pressure scale in the previous study . The overpressure was calculated using these boundaries. We observed the pressure to drop during the transformation by 1-2 GPa, but this would not... more

by in situ X-ray observations based on the same pressure scale in the previous study . The overpressure was calculated using these boundaries. We observed the pressure to drop during the transformation by 1-2 GPa, but this would not affect the transformation rate significantly because the overpressure is very large in the present study. This has been confirmed in the post-spinel transformation 7 .

Sequential barcoded fluorescent in situ hybridization (seqFISH) allows large numbers of molecular species to be accurately detected in single cells, but multiplexing is limited by the density of barcoded objects. We present correlation... more

Sequential barcoded fluorescent in situ hybridization (seqFISH) allows large numbers of molecular species to be accurately detected in single cells, but multiplexing is limited by the density of barcoded objects. We present correlation FISH(corrFISH), a method to resolve dense temporal barcodes
in sequential hybridization experiments. Using corrFISH, we quantified highly expressed ribosomal protein genes in single cultured cells and mouse thymus sections, revealing
cell-type-specific gene expression.

High-throughput screening of physical, genetic and chemical-genetic interactions brings important perspectives in the Systems Biology field, as the analysis of these interactions provides new insights into protein/gene function, cellular... more

High-throughput screening of physical, genetic and chemical-genetic interactions brings important perspectives in the Systems Biology field, as the analysis of these interactions provides new insights into protein/gene function, cellular metabolic variations and the validation of therapeutic targets and drug design. However, such analysis depends on a pipeline connecting different tools that can automatically integrate data from diverse sources and result in a more comprehensive dataset that can be properly interpreted. We describe here the Integrated Interactome System (IIS), an integrative platform with a web-based interface for the annotation, analysis and visualization of the interaction profiles of proteins/genes, metabolites and drugs of interest. IIS works in four connected modules: (i) Submission module, which receives raw data derived from Sanger sequencing (e.g. two-hybrid system); (ii) Search module, which enables the user to search for the processed reads to be assembled...

This monographic issue of Current Pharmacological Design discusses extensively on the innovative paradigms for disease control in Active and Healthy Ageing. Wellness, as a status to be achieved and maintained in our lives, getting longer... more

This monographic issue of Current Pharmacological Design discusses extensively on the innovative paradigms for disease control in Active and Healthy Ageing. Wellness, as a status to be achieved and maintained in our lives, getting longer and hopefully healtier, is the new and comprehensive declination of "health" itself, leading the shaping of research and research policy in the health domain worldwide. Many of the contributions describe the state of the art -and beyond- approaches for the most common diseases based on the available medical knowledge; two, in particular (Bousquet J et al., Cesario A, et al.), extend to the innovative approaches defined in the framework of the holistic and integrative philosophy of the Predictive, Preventive, Personalized and Participatory (P4) Systems Medicine. The availability of more and more powerful technologies to extract data coupled with the inclusion of information coming from the nonstrictly-medical sphere of the patient/individua...

We propose the term ''synthetic tissue biology'' to describe the use of engineered tissues to form biological systems with metazoan-like complexity. The increasing maturity of tissue engineering is beginning to render this goal... more

We propose the term ''synthetic tissue biology'' to describe the use of engineered tissues to form biological systems with metazoan-like complexity. The increasing maturity of tissue engineering is beginning to render this goal attainable. As in other synthetic biology approaches, the perspective is bottom-up; here, the premise is that complex functional phenotypes (on par with those in whole metazoan organisms) can be effected by engineering biology at the tissue level. To be successful, current efforts to understand and engineer multicellular systems must continue, and new efforts to integrate different tissues into a coherent structure will need to emerge. The fruits of this research may include improved understanding of how tissue systems can be integrated, as well as useful biomedical technologies not traditionally considered in tissue engineering, such as autonomous devices, sensors, and manufacturing. Birth Defects Research (Part C) 81:354-361,

Systems biology approaches, such as kinetic modelling, could provide valuable insights into how thioredoxins, glutaredoxins and peroxiredoxins (here collectively called redoxins), and the systems that reduce these molecules are regulated.... more

Systems biology approaches, such as kinetic modelling, could provide valuable insights into how thioredoxins, glutaredoxins and peroxiredoxins (here collectively called redoxins), and the systems that reduce these molecules are regulated. However, it is not clear whether redoxins should be described as redox couples (with redox potentials) or as enzymes (with Michaelis-Menten parameters) in such approaches. We show that in complete redoxin systems, redoxin substrate saturation and other purported enzymatic behaviours result from limitations in the redoxin redox cycles in these systems. Michaelis-Menten parameters are therefore inappropriate descriptors of redoxin activity; data from redoxin kinetic experiments should rather be interpreted in terms of the complete system of reactions under study. These findings were confirmed by fitting kinetic models of the thioredoxin and glutaredoxin systems to in vitro datasets. This systems approach clarifies the inconsistencies with the descriptions of redoxins and emphasizes the roles of redoxin systems in redox regulation.

Modelos anteriores de la glico´lisis de la forma sangu´ınea de Trypanosoma brucei arrojaban valores de flujo coherentes con resultados experimentales, sin embargo asum´ıan una suma conservada de fosfatos y un balance energ´etico de cero en... more

Modelos anteriores de la glico´lisis de la forma sangu´ınea de Trypanosoma brucei arrojaban valores de flujo coherentes con resultados experimentales, sin embargo asum´ıan una suma conservada de fosfatos y un balance energ´etico de cero en el interior del glicosoma. En este trabajo se construyeron modelos de las formas sangu´ınea y proc´ıclica de Trypanosoma brucei y de la forma epimastigote de Trypanosoma cruzi que predicen valores de flujo glicol´ıtico similares a los reportados experimentalmente y permiten modelar condiciones de alto consumo de ATP y G6P, como rutas de s´ıntesis y ruta de las pentosas fosfato, presentes en los par´asitos pero ignoradas hasta el momento en la los modelos existentes en la literatura. El valor del flujo glicol´ıtico del modelo de la forma sangu´ınea de T. brucei fue de 91.08 nmol de glucosa/min/mg prot., para la forma proc´ıclica de 6.99 nmol de glucosa/min/mg prot., ambos valores dentro del rango de los resultados experimentales. Ambos modelos alcanzan el estado estacionario para todas las variables, en el caso del modelo de la forma proc´ıclica es necesario introducir los t´erminos de consumo de ATP y G6P en el sistema de ecuaciones para evitar la acumulaci´on de fructosa-1,6-bisfosfato. Las proporciones de productos finales fueron similares a las experimentales tanto en el modelo de la forma sangu´ınea como en el modelo de la forma proc´ıclica. Los valores de concentracio´n de los metabolitos fueron similares a los reportados en la literatura, una mejor estimacio´n que la de modelos anteriores. Se determin´o que la produccio´n de succinato en el modelo de la forma proc´ıclica esta´ ligada al balance redox de la c´elula y a la velocidad del transporte de triosas hacia y desde la mitocondria. Se demostro´ mediante un modelo algebraico que la acumulacio´n de fructosa-1,6bisfosfato es una consecuencia directa de la configuraci´on del sistema. El que sea necesario introducir t´erminos de consumo en las ecuaciones para alcanzar el estado estacionario en todas las variables es un argumento a favor de considerar el glicosoma como una organela de s´ıntesis.

MicroRNAs (miRNAs) are involved in many regulatory pathways some of which are complex networks enriched in regulatory motifs like positive or negative feedback loops or coherent and incoherent feedforward loops. Their complexity makes the... more

MicroRNAs (miRNAs) are involved in many regulatory pathways some of which are complex networks enriched in regulatory motifs like positive or negative feedback loops or coherent and incoherent feedforward loops. Their complexity makes the understanding of their regulation dif fi cult and the interpretation of experimental data cumbersome. In this book chapter we claim that systems biology is the appropriate approach to investigate the regulation of these miRNA-regulated networks. Systems biology is an interdisciplinary approach by which biomedical questions on biochemical networks are addressed by integrating experiments with mathematical modelling and simulation. We here introduce the foundations of the systems biology approach, the basic theoretical and computational tools used to perform model-based analyses of miRNA-regulated networks and review the scienti fi c literature in systems biology of miRNA regulation, with a focus on cancer. Keywords miRNA regulated networks • miRNA target hub • miRNA cluster • Feedback loop • Feedforward loop • Post-transcriptional regulation • miRNA network motifs • Kinetic models • Bistability • Ultrasensitivity

With the continuous development, in the last decades, of analytical techniques providing complex information at single cell level, the study of cell heterogeneity has been the focus of several research projects within analytical... more

With the continuous development, in the last decades, of analytical techniques providing complex information at single cell level, the study of cell heterogeneity has been the focus of several research projects within analytical biotechnology. Nonetheless, the complex interplay between environmental changes and cellular responses is yet not fully understood, and the integration of this new knowledge into the strategies for design, operation and control of bioprocesses is far from being an established reality. Indeed, the impact of cell heterogeneity on productivity of large scale cultivations is acknowledged but seldom accounted for. In order to include population heterogeneity mechanisms in the development of novel bioprocess control strategies, a reliable mathematical description of such phenomena has to be developed. With this review, we search to summarize the potential of currently available methods for monitoring cell population heterogeneity as well as model frameworks suitable for describing dynamic heterogeneous cell populations. We will furthermore underline the highly important coordination between experimental and modeling efforts necessary to attain a reliable quantitative description of cell heterogeneity, which is a necessity if such models are to contribute to the development of improved control of bioprocesses.