ComplexDis list of deliverables
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D1: We have provided team partners with annotated sets of putatively co-regulated
allergy-specific genes. We have completed a comprehensive paper on computational
tools for clustering.
D2: We have synthesized a graph analysis software, and implemented it on a variety
of platforms.
D3: We have taken steps to make our codes more user friendly, and made them on
them available in the public domain. We have conducted sensitivity analysis to
evaluate parameter tuning strategies (http://grappa.eecs.utk.edu/welcome.php)
D4: We are currently preparing a paper on graph algorithms toolkits and applications.
D5: Software and database (prototype 1). Hubs of biological entities have been
mined, clustered from the literature, and classified by their relationships to the
complex diseases of focus in the project. This has been Delivered month 6 on its
expected due date.
D6: Publication on the study of the topology robustness of literature networks and the
analysis of such networks to leading to the identification of putative critical hubs
responsible for the topology of the disease gene network.
D7: Software and database solution (prototype 2) that allows for the knowledge
discovery and analysis of high-throughput biological data from our project partners.
This has been delivered month 12 on its expected due date.
D8: Publication on a study that validates the text-mining and NLP algorithms to
capture the modular organization of cellular components from the literature and the
analysis of high-throughput biological data using the modular organization database.
This will be delivered on month 36 on its expected due date.
D9: Vision paper on using recent work in language evolution. Due month 18. A
number of relevant publications appeared in a variety of journals and conference
proceedings, and a vision paper involving two other partners has been submitted to
the journal of Biosemiotics.
D10: Software that performs computer simulations. Due month 24. Regular releases
of the Babel2 simulation software platform that includes Fluid Construction Grammar
were (and continue to be) released through http://www.fcg-net.org. This software is
being used by a growing number of researchers.
D11: Comprehensive overview of how simulation results can be analyzed. This
mainly forms the subject of the paper, which is under revision and will be published
soon.
D12. The simulator it self. This deliverable consists in the computer model
relative to the agent-based simulation tool for the allergic reaction to a generic
allergen. This deliverable consists in the computer model relative to the agentbased simulation tool for the allergic reaction to a generic allergen.
The code is available under request to f.castiglione@iac.cnr.it.
D13. Technical report describing the architectural issues. In the first reporting
period WP4 has published the article Santoni et al., Implementation of a
regulatory gene network to simulate the Th1/2 differentiation in an agent-based
model of hypersensitivity reactions. Bioinformatics, 24: 1374-1380, 2008. In that
article we have describe the development of the simulation tool for the gene
regulatory network for the switch of Th cells and how we integrate it in the
agent-based meso-scopic simulator of type I allergic response (i.e., D12). The
work is one of the first attempts to integrate two mathematical or computational
descriptions of the meso-scopic cellular level of the immune system functions
(lymphocyte interaction, antigen presentation, humoral response, etc.) with a
microscopic gene-network dynamics represented by a Boolean-type dynamical
network.
This article together with D13 makes up a full report describing the main
features of the simulator D12
D14. Visualization tools and various statistical utilities. The simulator D12 is
equipped with two graphical modules.
The first of the two facilitates input of the parameters of the simulation also
providing a consistency check on the values (Figure 2 left-panel of the section
relative to WP4 of the activity report). A simple interface to gnuplot allows
plotting output data as for example distributions or cell population dynamics
(Figure 2, right-panels of the section relative to WP4 of the activity report).
To this purpose a set of scripts to generate graphical outputs to the screen or on image
files have been provided.
The second graphical module allows the user to display 3D data (this is used only
in the Multiple Sclerosis project described in the activity report). The tool
visualizes each lattice point of the virtual organ as a dot. Its colour represents the
concentration of the agent’s population that has been selected by the user by the
appropriate lever
D15: Description of emergence of new network modules in allergen-stimulated CD4
+ T cells from unselected patients with allergic rhinitis- journal publications and
workshops have been delivered. In addition a study of genetic variants has been
performed (Mobini et al BMC sys bio 2009, Benson et al. Allergy 2009)
D16: Description of customized DNA microarray gene chip for allergy research- We
have defined a transcriptomal module that can be used for customized gene chips
(Barrenäs et al, submitted)
D17: Detailed mechanistic description of subtypes of transcriptional modules that
may be specific for different European populations. Identification of protein markers
for these modules- journal publication and workshop. Large materials (n>200) of
allergen-challenged CD4 + cells from allergic patients, including monozygous twins
have been collected in Italy and Sweden. Gene expression microarray analyses have
been performed and two articles describing protein markers described (Wang et al. J
Allergy Clin Immunol 2009, Wang et al, submitted)
D18. Description and validation of key modules and genes in a specific subtype studied
under different conditions-journal publication and workshop (month 36). Using combined
gene expression- and ChIP-chip microarrays together with sequence-based predictions we
have identified a key transcription factor (TF) and its targets in allergen-challenged CD4
+ cells. The TF was validated by RNAi – mediated knockdown; first in relation to the
Th2 cytokines IL-5 and IL-13 and next by pathway analysis of gene expression
microarray data (Mobini et al, in manuscript)
D19. Description of a multi-layer model of a network module that encompasses the
DNA, mRNA and protein level (month 36). We have defined a model that includes DNA,
mRNA and protein levels based on analysis of allergen-challenged CD4 + cells.
D20: Identification of markers for treatment response in allergen-challenged Th cells
– journal publication. Status - Completed. Article ready by next month in spite of the
delay in achieving the planned twins number due to very strict inclusion criteria
D21: Identification of markers for treatment response in nasal fluids from twins with
allergic rhinitis – journal publication. Status – Completed.
Article ready by next month
D22: Analysis of predictive value of markers for treatment response in nasal fluids
from unselected patients with allergic rhinitis – journal publication. Status –
completed (Wang et al, submitted).
D23 (and M16). Blood samples from more than 900 patients with seasonal allergic
rhinitis and controls have been obtained, and DNA extracted for SNP analysis by
WP5 (which has already analysed other materials consisting of more than 5000
subjects. This has resulted in one publication (Benson et al. Allergy 2009, and
Barrenäs et al, submitted)
D24. As WP5 has the experience and protocols to reach D24 in time, D24 has been
shifted from WP7 to WP5, that together with WP1 have long experience of this type
of work. Instead WP7 performs a study aiming to find markers for response to
treatment with local glucocorticoids in patients with intermittent allergic rhinitis. This
is done by analyzing nasal fluid protein markers in patients that do and do not respond
to treatment. Selected patients, representing both categories have been analysed and
markers described in a manuscript that will soon be submitted.
D25. A set of biological pathways involved in MS pathogenesis:
1. Description of a set of gene expression patterns and modules associated with MS.
Submission to public databases and journal publication (month 18):
We have identified a set of immune and non-immune pathways differentially
overrepresented in MS and we have validated one of then (neurotrophins pathway) in
the animal model of MS
2. Description of new dynamics associated with the development of MS. journal
publication and workshop (month 24):
We have found that the negative feed-back provided by regulatory T-cells is critical
for establishing the prototypical relapsing-remitting dynamics in MS (Velez et al.
Under review) workshop on systems biology Barcelona October 2010
D26. New mathematical and computational tools for analyzing the dynamics and
robustness of evolving networks. Workshops and consortia web diffusion (month 30):
ASPI, COMPUTEGTOM, switching-random walker algorithm. New mathematical
and computational tools for analyzing the dynamics and robustness of evolving
networks. (due date of submission: month 18) Status - Research done, most of the
publications and the results dissemination done. Hierarchy measures and entropy in
directed graphs are articles in preparation. Submission in the next months. Workshop
on systems biology Barcelona 2010
D27. A set of biological markers to monitor response to immunomodulatory therapy
(IFNB) and candidate therapeutic pathways (which will require further validation).
Journal publication and workshop (month 36): Jagged-Notch pathway, neurotrophin
pathway
Workshop on systems biology Barcelona 2010
D28: Topological analysis of MS network:
Analysis of the gene expression patterns and IP modules associated with MS.
Submission to public databases and journal publication (due date of submission:
month 24) Status - Computation implementation done. Preliminary version of MS
network and immune system network was obtained in a computational approach in
collaboration with Dr. Villoslada's group. Preliminary results in WP7 scientific report.
Analysis of new dynamics associated with the development of MS. Workshops and
consortia web diffusion. (due date of submission: month 30) Status - Preliminary
analysis of network topology for MS network and immune system network done.
Details in WP7 scientific report. Pending of experimental validation