TY  - JOUR
A1  - Salihoglu, Rana
A1  - Srivastava, Mugdha
A1  - Liang, Chunguang
A1  - Schilling, Klaus
A1  - Szalay, Aladar
A1  - Bencurova, Elena
A1  - Dandekar, Thomas
T1  - PRO-Simat: Protein network simulation and design tool
JF  - Computational and Structural Biotechnology Journal
N2  - PRO-Simat is a simulation tool for analysing protein interaction networks, their dynamic change and pathway engineering. It provides GO enrichment, KEGG pathway analyses, and network visualisation from an integrated database of more than 8 million protein-protein interactions across 32 model organisms and the human proteome. We integrated dynamical network simulation using the Jimena framework, which quickly and efficiently simulates Boolean genetic regulatory networks. It enables simulation outputs with in-depth analysis of the type, strength, duration and pathway of the protein interactions on the website. Furthermore, the user can efficiently edit and analyse the effect of network modifications and engineering experiments. In case studies, applications of PRO-Simat are demonstrated: (i) understanding mutually exclusive differentiation pathways in Bacillus subtilis, (ii) making Vaccinia virus oncolytic by switching on its viral replication mainly in cancer cells and triggering cancer cell apoptosis and (iii) optogenetic control of nucleotide processing protein networks to operate DNA storage. Multilevel communication between components is critical for efficient network switching, as demonstrated by a general census on prokaryotic and eukaryotic networks and comparing design with synthetic networks using PRO-Simat. The tool is available at https://prosimat.heinzelab.de/ as a web-based query server.
KW  - network simulation
KW  - protein analysis
KW  - signalling pathways
KW  - dynamic protein-protein interactions
KW  - optogenetics
KW  - oncolytic virus
KW  - DNA storage
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-350034
SN  - 2001-0370
VL  - 21
ER  - 
TY  - JOUR
A1  - Osmanoglu, Özge
A1  - Gupta, Shishir K.
A1  - Almasi, Anna
A1  - Yagci, Seray
A1  - Srivastava, Mugdha
A1  - Araujo, Gabriel H. M.
A1  - Nagy, Zoltan
A1  - Balkenhol, Johannes
A1  - Dandekar, Thomas
T1  - Signaling network analysis reveals fostamatinib as a potential drug to control platelet hyperactivation during SARS-CoV-2 infection
JF  - Frontiers in Immunology
N2  - Introduction 
Pro-thrombotic events are one of the prevalent causes of intensive care unit (ICU) admissions among COVID-19 patients, although the signaling events in the stimulated platelets are still unclear.

Methods 
We conducted a comparative analysis of platelet transcriptome data from healthy donors, ICU, and non-ICU COVID-19 patients to elucidate these mechanisms. To surpass previous analyses, we constructed models of involved networks and control cascades by integrating a global human signaling network with transcriptome data. We investigated the control of platelet hyperactivation and the specific proteins involved.

Results
Our study revealed that control of the platelet network in ICU patients is significantly higher than in non-ICU patients. Non-ICU patients require control over fewer proteins for managing platelet hyperactivity compared to ICU patients. Identification of indispensable proteins highlighted key subnetworks, that are targetable for system control in COVID-19-related platelet hyperactivity. We scrutinized FDA-approved drugs targeting indispensable proteins and identified fostamatinib as a potent candidate for preventing thrombosis in COVID-19 patients.

Discussion 
Our findings shed light on how SARS-CoV-2 efficiently affects host platelets by targeting indispensable and critical proteins involved in the control of platelet activity. We evaluated several drugs for specific control of platelet hyperactivity in ICU patients suffering from platelet hyperactivation. The focus of our approach is repurposing existing drugs for optimal control over the signaling network responsible for platelet hyperactivity in COVID-19 patients. Our study offers specific pharmacological recommendations, with drug prioritization tailored to the distinct network states observed in each patient condition. Interactive networks and detailed results can be accessed at https://fostamatinib.bioinfo-wuerz.eu/.
KW  - signaling network
KW  - controllability
KW  - platelet
KW  - SARS-CoV-2
KW  - fostamatinib
KW  - drug repurposing
KW  - COVID-19
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-354158
VL  - 14
ER  -