Baltazar D. Aguda

Philippine Genome Center

An increasing number of transcription factors (TFs) and microRNAs (miRNAs) is known to form feedback loops (FBLs) of interactions where a TF positively or negatively regulates the expression of a miRNA, and the miRNA suppresses the translation of the TF messenger RNA. FBLs are potential sources of instability in a gene regulatory network. Positive...

A kinetic model of a molecular control system for the cellular decision to proliferate or differentiate is formulated and analyzed for the purpose of understanding how the system can break down in cancer cells. The proposed core of this control system is composed of the transcription factors Myc and p53. The network of interactions between these fa...

The transcription factors E2F and Myc participate in the control of cell proliferation and apoptosis, and can act as oncogenes or tumor suppressors depending on their levels of expression. Positive feedback loops in the regulation of these factors are predicted-and recently shown experimentally-to lead to bistability, which is a phenomenon characte...

A detailed model of the G(2) DNA damage checkpoint (G2DDC) system is presented that includes complex regulatory networks of the mitotic kinase Cdc2, phosphatase Cdc25, Wee1 kinase, and damage signal transduction pathways involving Chk1 and p53. Assumptions on the kinetic equations of the G2DDC are made, and computer simulations are carried out to d...

A detailed model mechanism for the G1/S transition in the mammalian cell cycle is presented and analysed by computer simulation to investigate whether the kinetic origins of the restriction point (R-point) can be identified. The R-point occurs in mid-to-late G1 phase and marks the transition between mitogen-dependent to mitogen-independent progress...

The restriction point marks a switch in G1 from growth factor-dependent to growth factor-independent progression of the cell cycle. The proper regulation of this switch is important for normal cell processes; aberrations could result in a number of diseases such as cancer, neurodegenerative disorders, stroke and myocardial infarction. To further un...

Ovarian cancer is one of the most lethal cancers in the female reproductive system. Our previous study has shown that ovarian cancer may be initiated by ovarian cancer initiating cells (OCIC) characterized by the surface antigen CD44 and c-KIT (CD117). Previous study also suggested that long term treatment of estrogen such as hormonal replacement t...

We propose the hypothesis that for a particular type of cancer there exists a key pair of oncogene (OCG) and tumor suppressor gene (TSG) that is normally involved in strong stabilizing negative feedback loops (nFBLs) of molecular interactions, and it is these interactions that are sufficiently per- turbed during cancer development. These nFBLs are...

We propose the hypothesis that for a particular type of cancer there exists a key pair of oncogene (OCG) and tumor suppressor gene (TSG) that is normally involved in strong stabilizing negative feedback loops (nFBLs) of molecular interactions, and it is these interactions that are sufficiently perturbed during cancer development. These nFBLs are th...

The current understanding of the mechanism and kinetics of the G1 checkpoint called the restriction point (R‐point) in mammalian cells is discussed. The core mechanism involves a network of interactions among transcription factors (Myc and E2F) and cyclin‐dependendent kinases (CcnD/Cdk4,6 and CcnE/Cdk2). This network contains many positive feedback...

Accumulating data indicate that cancer stem cells contribute to tumor chemoresistance and their persistence alters clinical outcome. Our previous study has shown that ovarian cancer may be initiated by ovarian cancer initiating cells (OCIC) characterized by surface antigen CD44 and c-KIT (CD117). It has been experimentally demonstrated that a micro...

Presented at: International Congress of Mathematicians 2014, 13 - 21 Aug 2014, OP-17-1689 Also available here: http://f1000.com/posters/browse/summary/1096536

Kras and Ink4a are involved in negative feedback loops (nFBLs) of interactions that presumably prevent overshooting of Kras activity when stimulated by growth factors. These nFBLs are composed of pathways of Kras-induced upregulation of Ink4a coupled with pathways of Ink4a-mediated downregulation of Kras. The operation of these nFBLs is perturbed w...

Old version can be downloaded from: http://www.ma.utexas.edu/mp_arc/c/13/13-79.pdf A Simple Mathematical Model Explaining Deterministic Cellular Reprogramming Using External Stimulus, we also show possibility of oscillation (eg, repressilator): Non-binary simultaneous decision network of gene regulation represents a cell differentiation process...

With increasing knowledge of cellular networks of gene and molecular interactions, and their alterations in GBM (glioblastoma multiforme), it is now possible to apply methods of Network Pharmacology (NP) to predict candidate drug targets for this malignant brain tumor. NP requires the development of mathematical methods for network stability and pe...

Steady state of T (Ts) as a function of fT (from Eqn 2) for two values of θT (θT = 1 for the black curve, and θT = 0.5 for the gray curve). Other parameter values: bT = 0.05, eT = 1. (TIF)

The detailed immune network model, showing numbered interactions representing the model differential equations for each cell [T effector (T), Treg (R), Macrophage (M)] or molecule (TNFα, IFNγ, IL-2), represented by Eqns 3–8. Arrows mean “upregulate” or activate while hammerheads mean “downregulate” or inhibit. (TIF)

Supporting information demonstrating a bistable switch between low and high Teff steady states predicted by the model. (DOC)

Sarcoidosis is a polygenic disease with diverse phenotypic presentations characterized by an abnormal antigen-mediated Th1 type immune response. At present, progress towards understanding sarcoidosis disease mechanisms and the development of novel treatments is limited by constraints attendant to conducting human research in a rare disease in the a...

An apparatus for the study of the discharge patterns generated in gaseous dielectric breakdown is described. The discharge patterns are imaged using a fast optical imaging system (≈ 40 ns exposure time) and are found to be fractals. The experimental fractal dimension obtained using a +17 kV pulse in air at atmospheric pressure is Dexpt ≈ 1.8 ± 0.1,...

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

[This corrects the article on p. e3694 in vol. 3.].

Chromosomal abnormalities, immunoglobulin heavy chain variable-region (IGHV) gene mutation status, and zeta-associated protein 70 (ZAP-70) expression levels have independent prognostic relevance in chronic lymphocytic leukemia (CLL); however, their concordance is variable. Because deregulation of microRNAs has been linked to disease initiation and...

Id2 is a member of the helix-loop-helix (HLH) family of transcription regulators known to antagonize basic HLH transcription factors and proteins of the retinoblastoma tumor suppressor family and is implicated in the regulation of proliferation, differentiation, apoptosis and carcinogenesis. To investigate its proposed role in tumorigenesis, Id2 or...

Chondrogenesis of mesenchymal cells in 3-D culture. C3H10T1/2 cells were cultured in electrospun scaffolds for 48 hours and the proteoglycan synthesis was assessed by Alcian blue staining (A), gene expression by real time RT-PCR (B), and protein expression by Western blot (C). (A) The cell-scaffold constructs showed the presence of proteoglycan syn...

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Intracellular protein levels of p53 and MDM2 have been shown to oscillate in response to ionizing radiation (IR), but the physiological significance of these oscillations remains unclear. The p53-MDM2 negative feedback loop -- the putative cause of the oscillations -- is embedded in a network involving a mutual antagonism (or positive feedback loop...

During normal physical activities cartilage experiences dynamic compressive forces that are essential to maintain cartilage integrity. However, at non-physiologic levels these signals can induce inflammation and initiate cartilage destruction. Here, by examining the pro-inflammatory signaling networks, we developed a mathematical model to show the...

Predicted targets for miRNAs expressed in the plasma microvesicles and PBMC. Predicted targets were compiled separately using Sanger miRBase and TargetScan for the top nine miRNAs expressed in the plasma microvesicles and PBMC (Table 1). Targets were common between the databases were furthered analyzed for predicted function. (0.20 MB PDF)

Normalized expression for plasma microvesicles and PBMC. Expression of miRNAs in the plasma microvesicles and PBMC were analyzed separately (n = 51). The normalized miRNA expression was generated using median normalization analysis then the mean CT value was converted to expression (2∧(−deltaCT)) ±standard deviation (S.D.). (0.01 MB PDF)

Comparison of miRNA expression between plasma microvesicles and PBMC. In order to test the differences of miRNA expression between plasma microvesicles and PBMC, data were analyzed using linear mixed models. The p-values were generated from the model based on the estimated difference and sample variation. A bonferroni adjustment for multiple compar...

MicroRNAs (miRNA) are small non-coding RNAs that regulate translation of mRNA and protein. Loss or enhanced expression of miRNAs is associated with several diseases, including cancer. However, the identification of circulating miRNA in healthy donors is not well characterized. Microvesicles, also known as exosomes or microparticles, circulate in th...

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The monolayer of endothelial cells (ECs) lining the inner wall of blood vessels deteriorates as a person ages due to a complex interplay of a variety of causes including cell death arising from shear stress of blood flow and cellular oxidative stress, cellular senescence, and decreased rate of replacement of dead ECs by progenitor stem cells. A con...

Depending on the nature of extracellular stimuli and the ensuing intracellular signal transduction pathways, certain transcription factors are activated and subsequently determine the extent of expression of genes involved in cell proliferation, survival, and death. These factors are referred to as transcriptional control nodes because they permit...

The tumor suppressor protein, p53, and the oncoprotein, Akt, are involved in a cross talk that could be at the core of a cell's control machinery for switching between survival and death. This cross talk is a combination of reciprocally antagonistic pathways emanating from p53 and Akt, and also involves another tumor suppressor gene, PTEN, and anot...

The ability of an organism to reproduce and perpetuate its species is one of life’s defining attributes. As far as we know of all life forms on earth, the replication of a set of genetic information encoded in the DNA is absolutely required. Because of stringent requirements for faithful gene replication and the uncertainty in environmental conditi...

The cell-division cycle and apoptosis are key cellular processes deregulated during carcinogenesis. Recent work of Aguda and Algar suggests a modular organization of regulatory molecular pathways linking the cellular processes of division and apoptosis. We carry out a detailed mathematical analysis of the Aguda-Algar model to unravel the dynamics i...

IntroductionFormal Representation of GRNsAn Example of a GRN: The Lac OperonHierarchies of GRN Models: From Probabilistic Graphs to Mechanistic ModelsA Guide to Databases and Knowledgebases on the InternetPathway Databases and PlatformsOntologies for GRN Modeling Current gene, Interaction, and Pathway OntologiesWhole-cell Modeling PlatformsOntology...

We predict that computational modeling platforms will soon become stan- dard tools in experimental laboratories involved in the study of complex regu- latory networks of various cellular processes—a field of research where an avalanche of genomic, proteomic and other biochemical data have recently been gleaned, and this trend is expected to continu...

This paper proposes an integration and modular organization of the complex regulatory networks involved in the mammalian cell cycle, apoptosis, and related intracellular signaling cascades. A common node linking the cell cycle and apoptosis permits the possibility of coordinate control between the initiation of these two cellular processes. From th...

The essential genes, proteins and associated regulatory networks involved in the entry into the mammalian cell cycle are identified, from activation of growth-factor receptors to intracellular signal transduction pathways that impinge on the cell cycle machinery and ultimately on the initiation of DNA replication. Signaling pathways mediated by the...

A detailed model of the G2 DNA damage checkpoint (G2DDC) system is presented that includes complex regulatory networks of the mitotic kinase Cdc2, phosphatase Cdc25, Wee1 kinase, and damage signal transduction pathways involving Chk1 and p53. Assumptions on the kinetic equations of the G2DDC are made, and computer simulations are carried out to dem...

The G2-M checkpoint in the cell cycle is identified with a set of phosphorylation-dephosphorylation (PD) cycles involving Cdc25 and the maturation-promoting factor (MPF); these PD cycles are coupled in a way that generates an instability. This instability arises out of a transcritical bifurcation which could be exploited by the G2 DNA damage checkp...

The dynamics of locally and globally coupled cells that convert a substrate to a product via an uncompetitive substrate-inhibition mechanism is studied. When the cell-cell coupling strength is below a threshold value, the coupled system exhibits a large number of steady states; however, all cells cluster to one state when coupling exceeds the thres...

It is shown experimentally that the rate of change upsilon of the applied potential affects the delay associated with the Hopf and saddle-node bifurcations in the anodic nickel dissolution in aqueous sulfuric acid solutions. The magnitude of the delay is proportional to upsilon(p) where p approximate to 1 for the Hopf and p approximate to 2/3 for t...

A model mechanism for the phenol-inhibited peroxidase-catalyzed oxidation of indole-3-acetic acid (IAA) is proposed and analyzed. The model involves an autocatalytic free radical species that sustains IAA oxidation and the phenolic inhibitor acting as a free radical scavenger. Under a fixed set of parameter values, the model exhibits a coexistence...

General expressions are derived for the critical wave numbers for two- and three-species reaction mechanisms when their homogeneous steady states are destabilized by a relative flow of at least one species. Analysis of a model of the oscillating peroxidase–oxidase reaction indicates that the reaction exhibits this kind of instability. Computer simu...

A wide-ranging study of the effect of free-radical initiators, especially i-octyl nitrate and di-t-butyl peroxide, on the spontaneous ignition of diesel fuel is reported. The important kinetic processes induced by these additives occur in the gas phase, and not in the liquid droplets. Di-t-butyl and i-octyl nitrate peroxide work in different ways:...

A comparison is made between the reversible and irreversible formulations for a series of model isomerization reactions, and the conditions under which the differences are important are demonstrated.

Computer simulations of a detailed mechanism of the peroxidase-oxidase reaction show periodic-chaotic sequences for some ranges of enzyme concentrations. The mechanism involves two coupled feedback cycles that are both driven by oxygen. One of these cycles is the peroxidase catalytic cycle while the other is a conservation cycle involving all five...

A detailed mechanism for the aerobic oxidation of NADH catalyzed by horseradase peroxidase, called the peroxidase-oxidase reaction, is studied by computer simulation and found to show bistability, damped and sustained oscillations. These oscillations are smooth and almost sinusoidal. The mechanism also predicts that a stable oscillatory state and a...

Three dynamic elements, DE‐1, DE‐2, and DE‐3, are identified for the four‐species Olsen model of the peroxidase–oxidase reaction. DE‐1 is the damped Lotka oscillator which tends to generate smaller amplitude oscillations. DE‐2 is a switch responsible for the transitions between a small and a larger amplitude oscillation. DE‐3 is the reversible flux...

Two dynamic elements of the Willamowski–Rössler network are identified: one of which is a Lotka–Volterra oscillator involving two autocatalytic species X and Y, while the other is a switch between X and a third autocatalytic species Z. These two dynamic elements are coupled via X. Nonperiodic oscillations arise only if X autocatalyzes faster than Z...

Diatom shells are intricate structures made by single algal cells with a spacing between parts of about 0.1 mu m. They appear to be formed by instabilities in diffusion-limited precipitation of amorphous, colloidal silica. The patterns are apparently modified by surface diffusion during their formation. They present a possible means of microfabrica...

An examination of the complex oscillations and chaotic behavior observed in a model of the peroxidase‐catalyzed oxidation of NADH is made via numerical simulation and a fast/slow variable analysis. The NADH is considered to be a slowly varying species, compared to oxygen and the two key free‐radical intermediates in the mechanism. By considering NA...

The steady and oscillatory states of the Olsen and Degn model for the peroxidase–oxidase oscillator are found. The stability of the steady states is determined, and a bifurcation diagram for the oscillatory regime is found. A complex sequence of multiply periodic oscillations is observed and found to follow an orderly pattern when described via the...

Starting with a comprehensive list of elementary steps in the mechanism of the peroxidase–oxidase (PO) reaction, we extract the part of the mechanism essential to the experimentally observed bistability. A general systematic method is used to sort out the mechanism. First the extreme currents are found and the structure of the current polytope is d...

words): This tutorial will first provide a primer on online pathway resources and ontologies. The focus will then shift to the topics of extracting network models from pathways databases, modeling at different levels of resolution, the methods and tools of network analysis and simulation, and on the qualitative analysis of networks with incomplete...

This textbook originates from many years of combined research and teaching by the authors at the interfaces of mathematics, chemistry and biology. Several chapters grew out of two of Professor Aguda's university courses, one on 'self-organization in far-from- equilibrium chemical reaction systems' and the other on 'mechanisms and models of cellular...