Modeling the effect of environmental cytokines, nutrient conditions and hypoxia on CD4 T cell differentiation.

Upon antigen stimulation and co-stimulation, CD4 T lymphocytes produce soluble factors that promote the activity of other immune cells against pathogens or modified tissues; this task must be performed in presence of a variety of environmental cytokines, nutrient, and oxygen conditions, which necessarily impact T cell function. The complexity of the early intracellular processes taking place upon lymphocyte stimulation is addressed by means of a mathematical model based on a network that integrates variable microenvironmental conditions with intracellular activating, regulatory, and metabolic signals. Besides the phenotype subsets considered in previous works (Th1, Th2, Th17, and Treg) the model includes the main early events in differentiation to the T phenotype.

Continuous Modeling of T CD4 Lymphocyte Activation and Function.

T CD4+ cells are central to the adaptive immune response against pathogens. Their activation is induced by the engagement of the T-cell receptor by antigens, and of co-stimulatory receptors by molecules also expressed on antigen presenting cells. Then, a complex network of intracellular events reinforce, diversify and regulate the initial signals, including dynamic metabolic processes that strongly influence both the activation state and the differentiation to effector cell phenotypes.

An Integrative Network Modeling Approach to T CD4 Cell Activation.

The adaptive immune response is initiated by the interaction of the T cell antigen receptor/CD3 complex (TCR) with a cognate peptide bound to a MHC molecule. This interaction, along with the activity of co-stimulatory molecules and cytokines in the microenvironment, enables cells to proliferate and produce soluble factors that stimulate other branches of the immune response for inactivation of infectious agents. The intracellular activation signals are reinforced, amplified and diversified by a complex network of biochemical interactions, and includes the activity of molecules that modulate the activation process and stimulate the metabolic changes necessary for fulfilling the cell energy demands.

From Discrete to Continuous Modeling of Lymphocyte Development and Plasticity in Chronic Diseases.

The molecular events leading to differentiation, development, and plasticity of lymphoid cells have been subject of intense research due to their key roles in multiple pathologies, such as lymphoproliferative disorders, tumor growth maintenance and chronic diseases. The emergent roles of lymphoid cells and the use of high-throughput technologies have led to an extensive accumulation of experimental data allowing the reconstruction of gene regulatory networks (GRN) by integrating biochemical signals provided by the microenvironment with transcriptional modules of lineage-specific genes. Computational modeling of GRN has been useful for the identification of molecular switches involved in lymphoid specification, prediction of microenvironment-dependent cell plasticity, and analyses of signaling events occurring downstream the activation of antigen recognition receptors.

A physico-genetic module for the polarisation of auxin efflux carriers PIN-FORMED (PIN).

Intracellular polarisation of auxin efflux carriers is crucial for understanding how auxin gradients form in plants. The polarisation dynamics of auxin efflux carriers PIN-FORMED (PIN) depends on both biomechanical forces as well as chemical, molecular and genetic factors. Biomechanical forces have shown to affect the localisation of PIN transporters to the plasma membrane.

Statistical correlation of nonconservative substitutions of HIV gp41 variable amino acid residues with the R5X4 HIV-1 phenotype.

Background: The interaction of the envelope glycoprotein of HIV-1 (gp120/gp41) with coreceptor molecules has important implications for specific cellular targeting and pathogenesis. Experimental and theoretical evidences have shown a role for gp41 in coreceptor tropism, although there is no consensus about the positions involved. Here we analyze the association of physicochemical properties of gp41 amino acid residues with viral tropism (X4, R5, and R5X4) using a large set of HIV-1 sequences.

A Minimal Regulatory Network of Extrinsic and Intrinsic Factors Recovers Observed Patterns of CD4+ T Cell Differentiation and Plasticity.

CD4+ T cells orchestrate the adaptive immune response in vertebrates. While both experimental and modeling work has been conducted to understand the molecular genetic mechanisms involved in CD4+ T cell responses and fate attainment, the dynamic role of intrinsic (produced by CD4+ T lymphocytes) versus extrinsic (produced by other cells) components remains unclear, and the mechanistic and dynamic understanding of the plastic responses of these cells remains incomplete. In this work, we studied a regulatory network for the core transcription factors involved in CD4+ T cell-fate attainment.

Reshaping the epigenetic landscape during early flower development: induction of attractor transitions by relative differences in gene decay rates.

Background: Gene regulatory network (GRN) dynamical models are standard systems biology tools for the mechanistic understanding of developmental processes and are enabling the formalization of the epigenetic landscape (EL) model.

Methods: In this work we propose a modeling framework which integrates standard mathematical analyses to extend the simple GRN Boolean model in order to address questions regarding the impact of gene specific perturbations in cell-fate decisions during development.

Results: We systematically tested the propensity of individual genes to produce qualitative changes to the EL induced by modification of gene characteristic decay rates reflecting the temporal dynamics of differentiation stimuli.

Gene regulatory network models for floral organ determination.

Understanding how genotypes map unto phenotypes implies an integrative understanding of the processes regulating cell differentiation and morphogenesis, which comprise development. Such a task requires the use of theoretical and computational approaches to integrate and follow the concerted action of multiple genetic and nongenetic components that hold highly nonlinear interactions. Gene regulatory network (GRN) models have been proposed to approach such task.

Differences in HIV-1 viral loads between male and female antiretroviral-untreated Mexican patients.

Background And Aims: HIV-1 viral load is used to monitor AIDS progression and effect of antiretroviral therapy (ART). Several reports have indicated that the HIV-1 viral load of infected individuals is lower in females than in males. There are no reports exploring this issue in the Mexican population.

General theory of genotype to phenotype mapping: derivation of epigenetic landscapes from N-node complex gene regulatory networks.

We propose a systematic methodology to construct a probabilistic epigenetic landscape of cell-fate attainment associated with N-node Boolean genetic regulatory networks. The general derivation proposed here is exemplified with an Arabidopsis thaliana network underlying floral organ determination grounded on qualitative experimental data.

Single-cell and coupled GRN models of cell patterning in the Arabidopsis thaliana root stem cell niche.

Background: Recent experimental work has uncovered some of the genetic components required to maintain the Arabidopsis thaliana root stem cell niche (SCN) and its structure. Two main pathways are involved. One pathway depends on the genes SHORTROOT and SCARECROW and the other depends on the PLETHORA genes, which have been proposed to constitute the auxin readouts.

HIV-envelope-dependent cell-cell fusion: quantitative studies.

Interaction in vitro between cells infected with human immunodeficiency virus (HIV) and surrounding, uninfected, target cells often leads to cell fusion and the formation of multinucleated cells, called syncytia. The presence in HIV-infected individuals of virus strains able to induce syncytia in cultures of T cells is associated with disease progression and AIDS. Even in the asymptomatic stage of infection, multinucleated cells have been observed in different organs, indicating that fused cells may be generated and remain viable in the tissues of patients.