José C.M. Mombach

In silico network topology-based prediction of gene essentiality

The identification of genes essential for survival is important for the understanding of the minimal requirements for cellular life and for drug design. As experimental studies with the purpose of building a catalog of essential genes for a given organism are time-consuming and laborious, a computational approach which could predict gene essentiality with high accuracy would be of great value. We present here a novel computational approach, called NTPGE (Network Topology-based Prediction of Gene Essentiality), that relies on the network topology features of a gene to estimate its essentiality. The first step of NTPGE is to construct the integrated molecular network for a given organism comprising protein physical, metabolic and transcriptional regulation interactions. The second step consists in training a decision-tree-based machine-learning algorithm on known essential and non-essential genes of the organism of interest, considering as learning attributes the network topology information for each of these genes. Finally, the decision-tree classifier generated is applied to the set of genes of this organism to estimate essentiality for each gene. We applied the NTPGE approach for discovering the essential genes in Escherichia coli and then assessed its performance.

Cassie–Baxter to Wenzel state wetting transition: a 2D numerical simulation

We simulate in two dimensions the wetting behavior of a liquid droplet placed on a solid surface structured by a regular distribution of pillars. For this purpose, as in a recent study, we used the Potts Hamiltonian formalism. We focused our investigations on the transition between the wetting regimes characteristic of the super-repellent property of our surfaces. We determined several physical variables influencing such a property and we also built the wetting phase diagrams of which two different states and a transition zone were identified. The transition happens between a Cassie–Baxter state (CB) and the Wenzel state. We also show that the wetting transition is affected by fluctuations and liquid compressibility.

Cupin: A candidate molecular structure for the Nep1-like protein family

BackgroundNEP1-like proteins (NLPs) are a novel family of microbial elicitors of plant necrosis. Some NLPs induce a hypersensitive-like response in dicot plants though the basis for this response remains unclear. In addition, the spatial structure and the role of these highly conserved proteins are not known.ResultsWe predict a 3d-structure for the β-rich section of the NLPs based on alignments, prediction tools and molecular dynamics. We calculated a consensus sequence from 42 NLPs proteins, predicted its secondary structure and obtained a high quality alignment of this structure and conserved residues with the two Cupin superfamily motifs. The conserved sequence GHRHDWE and several common residues, especially some conserved histidines, in NLPs match closely the two cupin motifs. Besides other common residues shared by dicot Auxin-Binding Proteins (ABPs) and NLPs, an additional conserved histidine found in all dicot ABPs was also found in all NLPs at the same position.ConclusionWe propose that the necrosis inducing protein class belongs to the Cupin superfamily. Based on the 3d-structure, we are proposing some possible functions for the NLPs.

A Model for p38MAPK-Induced Astrocyte Senescence

Experimental evidence indicates that aging leads to accumulation of senescent cells in tissues and they develop a secretory phenotype (also known as SASP, for senescence-associated secretory phenotype) that can contribute to chronic inflammation and diseases. Recent results have showed that markers of senescence in astrocytes from aged brains are increased in brains with Alzheimer’s disease. These studies strongly involved the stress kinase p38MAPK in the regulation of the secretory phenotype of astrocytes, yet the molecular mechanisms underlying the onset of senescence and SASP activation remain unclear. In this work, we propose a discrete logical model for astrocyte senescence determined by the level of DNA damage (reparable or irreparable DNA strand breaks) where the kinase p38MAPK plays a central role in the regulation of senescence and SASP. The model produces four alternative stable states: proliferation, transient cycle arrest, apoptosis and senescence (and SASP) computed from its inputs representing DNA damages. Perturbations of the model were performed through gene gain or loss of functions and compared with results concerning cultures of normal and mutant astrocytes showing agreement in most cases. Moreover, the model allows some predictions that remain to be tested experimentally.

Induced genome maintenance pathways in pre-cancer tissues describe an anti-cancer barrier in tumor development

A recent model proposing that a barrier is raised against tumor evolution in pre-cancer tissues is investigated. For that we quantify expression alterations in genome maintenance pathways: DNA damage response, death pathways and cell cycle and also differentially expressed genes in transcriptomes of pre-cancerous and cancerous lesions deposited in the GEO database. We find that the main alterations in pre-cancer samples comprising the barrier are: (1) DNA double strand-breaks signaling and repair pathways induction, (2) upregulation of cyclin-dependent kinases, (3) p53 dependent (and independent) repair and apoptosis pathways induction and (4) replicative senescence induction early in tissue transformation. In the cancer samples we find that the induced pathways in pre-cancer are systematically inhibited and the only remaining induced pathway is p53, whereas the retinoblastoma pathway arises induced in most samples. The results give support to the model, furthermore they reveal the involvement of additional mechanisms in pre-cancer, including the early induction of replicative senescence and of p53 independent apoptosis.

Two-dimensional modeling of the superhydrophobic behavior of a liquid droplet sliding down a ramp of pillars

We present a two dimensional simulation based on the cellular Potts model of a liquid droplet sliding down a ramp of pillars. For the same critical angle at which a droplet starts to slide with minimal velocity on a smooth ramp in our simulation, we find that for a ramp of pillars the velocity of the droplet depends strongly on the solid fraction of contact (f). The velocity as a function of f has a maximum whose value is about 2.5 times higher than on a smooth surface, this corresponds to low values of the contact angle hysteresis (the difference between the advancing and receding contact angles of droplet measured on the ramp) consistent with superhydrophobic behavior.

The R implementation of the CRAN package PATHChange, a tool to study genetic pathway alterations in transcriptomic data

Tools that extract phenotype alterations from transcriptomic data are important to improve the interpretation of biological studies. PATHChange is a statistical CRAN package designed to work with data downloaded from the Gene Expression Omnibus database (GEO) to determine differential pathway expression in comparative studies including control samples. In this paper we present details of the structure, implementation and an example of use of the package.

An Ontology to Integrate Transcriptomics and Interatomics Data Involved in Gene Pathways of Genome Stability

Disruption of the mechanisms that regulate cell-cycle checkpoints, DNA repair, and apoptosis results in genomic instability and the development of cancer. The description of the complex network of these pathways requires news tools to integrate large quantities of experimental data in the design of biological information systems. In this context we present Ontocancro an extensible ontology and an architecture designed to facilitate the integration of data originating from different public databases in a single- and well-documented relational database. Ontocancro is an Ontology stored in a knowledge database designed to be a source of information to integrate transcriptomics and interatomics data involved in gene pathways of Genome Maintenance Mechanisms (GMM).

Can Nep1-like proteins form oligomers?

Nep1-like proteins (NLPs) are a novel family of microbial elicitors of plant necrosis that induce a hypersensitive-like response in dicot plants. The spatial structure and role of these proteins are yet unknown. In a paper published in BMC Plant Biology (2008; 8:50) we have proposed that the core region of Nep1-like proteins (NLPs) belong to the Cupin superfamily. Based on what is known about the Cupin superfamily, in this addendum to the paper we discuss how NLPs could form oligomers. Addendum to: Cechin AL, Sinigaglia M, Lemke N, Echeverrigaray S, Cabrera OG, Pereira GAG, Mombach JCM. Cupin: A candidate molecular structure for the Nep1-like protein family. BMC Plant Biol 2008; 8:50.

MicroRNA-16 feedback loop with p53 and Wip1 can regulate cell fate determination between apoptosis and senescence in DNA damage response

Cell fate regulation is an open problem whose comprehension impacts several areas of the biosciences. DNA damage induces cell cycle checkpoints that activate the p53 pathway to regulate cell fate mechanisms such as apoptosis or senescence. Experiments with different cell types show that the p53 pathway regulates cell fate through a switch behavior in its dynamics. For low DNA damage the pathway presents an oscillatory pattern associated with intense DNA damage repair while for high damage there are no oscillations and either p53 concentration increases inducing apoptosis or the cell enters a senescence state. Apoptosis and senescence phenotypes seem to have compensatory functions in tissues and the microRNA 16–1 (miR-16) is involved in the regulation of the fate between both phenotypes in cancer cells. To investigate the regulation of cell fate we developed a logical model of the G1/S checkpoint in DNA damage response that takes into account different levels of damage and contemplates the influence of miR-16 through its positive feedback loop formed with p53 and Wip1. The model reproduces the observed cellular phenotypes in experiments: oscillatory (for low DNA damage) regulated by negative feedback loops involving mainly p53 and Mdm2 and apoptotic or senescent (for high DNA damage) regulated by the positive p53/Wip1/miR-16 feedback loop. We find good agreement between the level of DNA damage and the probability of the phenotype produced according to experiments. We also find that this positive feedback makes senescent and apoptotic phenotypes to be determined stochastically (bistable), however controlling the expression level of miR-16 allows the control of fate determination as observed experimentally.