A signaling visualization toolkit to support rational design of combination therapies and biomarker discovery: SiViT

Targeted cancer therapy aims to disrupt aberrant cellular signalling pathways. Biomarkers are surrogates of pathway state, but there is limited success in translating candidate biomarkers to clinical practice due to the intrinsic complexity of pathway networks. Systems biology approaches afford better understanding of complex, dynamical interactions in signalling pathways targeted by anticancer drugs. However, adoption of dynamical modelling by clinicians and biologists is impeded by model inaccessibility. Drawing on computer games technology, we present a novel visualisation toolkit, SiViT, that converts systems biology models of cancer cell signalling into interactive simulations that can be used without specialist computational expertise. SiViT allows clinicians and biologists to directly introduce for example loss of function mutations and specific inhibitors. SiViT animates the effects of these introductions on pathway dynamics, suggesting further experiments and assessing candidate biomarker effectiveness. In a systems biology model of Her2 signalling we experimentally validated predictions using SiViT, revealing the dynamics of biomarkers of drug resistance and highlighting the role of pathway crosstalk. No model is ever complete: the iteration of real data and simulation facilitates continued evolution of more accurate, useful models. SiViT will make accessible libraries of models to support preclinical research, combinatorial strategy design and biomarker discovery

On the use of satellite Sentinel 2 data for automatic mapping of burnt areas and burn severity

In this paper, we present and discuss the preliminary tools we devised for the automatic recognition of burnt areas and burn severity developed in the framework of the EU-funded SERV_FORFIRE project. The project is focused on the set up of operational services for fire monitoring and mitigation specifically devised for decision-makers and planning authorities. The main objectives of SERV_FORFIRE are: (i) to create a bridge between observations, model development, operational products, information translation and user uptake; and (ii) to contribute to creating an international collaborative community made up of researchers and decision-makers and planning authorities. For the purpose of this study, investigations into a fire burnt area were conducted in the south of Italy from a fire that occurred on 10 August 2017, affecting both the protected natural site of Pignola (Potenza, South of Italy) and agricultural lands. Sentinel 2 data were processed to identify and map different burnt areas and burn severity levels. Local Index for Statistical Analyses LISA were used to overcome the limits of fixed threshold values and to devise an automatic approach that is easier to re-apply to diverse ecosystems and geographic regions. The validation was assessed using 15 random plots selected from in situ analyses performed extensively in the investigated burnt area. The field survey showed a success rate of around 95%, whereas the commission and omission errors were around 3% of and 2%, respectively. Overall, our findings indicate that the use of Sentinel 2 data allows the development of standardized burn severity maps to evaluate fire effects and address post-fire management activities that support planning, decision-making, and mitigation strategies.Fil: Lasaponara, Rosa. Consiglio Nazionale delle Ricerche; ItaliaFil: Tucci, Biagio. Consiglio Nazionale delle Ricerche; ItaliaFil: Ghermandi, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Instituto de Investigaciones en Biodiversidad y Medioambiente. Universidad Nacional del Comahue. Centro Regional Universidad Bariloche. Instituto de Investigaciones en Biodiversidad y Medioambiente; Argentina. Universidad Nacional del Comahue. Centro Regional Universitario Bariloche. Laboratorio de Ecotono; Argentin

Model-driven analysis of experimentally determined growth phenotypes for 465 yeast gene deletion mutants under 16 different conditions

An iterative approach that integrates high-throughput measurements of yeast deletion mutants and flux balance model predictions improves understanding of both experimental and computational results

Pan-active imidazolopiperazine antimalarials target the Plasmodium falciparum intracellular secretory pathway.

A promising new compound class for treating human malaria is the imidazolopiperazines (IZP) class. IZP compounds KAF156 (Ganaplacide) and GNF179 are effective against Plasmodium symptomatic asexual blood-stage infections, and are able to prevent transmission and block infection in animal models. But despite the identification of resistance mechanisms in P. falciparum, the mode of action of IZPs remains unknown. To investigate, we here combine in vitro evolution and genome analysis in Saccharomyces cerevisiae with molecular, metabolomic, and chemogenomic methods in P. falciparum. Our findings reveal that IZP-resistant S. cerevisiae clones carry mutations in genes involved in Endoplasmic Reticulum (ER)-based lipid homeostasis and autophagy. In Plasmodium, IZPs inhibit protein trafficking, block the establishment of new permeation pathways, and cause ER expansion. Our data highlight a mechanism for blocking parasite development that is distinct from those of standard compounds used to treat malaria, and demonstrate the potential of IZPs for studying ER-dependent protein processing

Resistance is Futile: Physical Science, Systems Biology and Single-Cell Analysis to Understanding the Plastic and Heterogeneous Nature of Melanoma and Their Role in Non-Genetic Drug Resistance

Melanoma is the most deadly form of skin cancer due to its great metastatic potential. Targeted therapy that inhibits the BRAF-V600E driver mutation has shown impressive initial responses in melanoma patients. However, drug resistance, as the universal phenomenon for any cancer therapy, always limits treatment efficacy and compromises outcomes. As the early-step of resistance development, non-genetic mechanisms enable cancer cells to transition into a drug-resistant state in as early as a few days after drug treatment without alteration of the genome. This early mechanism is, to a large extent, due to the heterogeneous and highly plastic nature of tumor cells. Therefore, it imperative to understand the plastic and heterogeneous nature of the melanoma cells in order to identify combination therapies that can overcome resistance. In this thesis, we investigate these two fundamental natures of non-genetic drug resistance using BRAF inhibition of BRAF-mutant melanomas as the model system. These melanoma cells undergo multi-step, reversible drug-induced cell-state transitions from the original sensitive phenotype to a drug-resistant one. We first conducted bulk analysis to characterize the detailed kinetics of the entire transition from drug-sensitive state towards drug-resistant state, revealing expression changes of thousands of genes and extensive chromatin remodeling. A 3-step computational biology approach greatly simplified the complexity and revealed that the whole cell-state transition was controlled by a gene module activated within just the first three days of drug treatment, with the RelA transcription factor driving chromatin remodeling to establish an epigenetic program encoding long-term phenotype changes towards resistance. From there, a detailed mechanism connecting tumor epigenetic plasticity with non-genetic drug resistance was resolved through in-depth molecular biology experiments. The mechanism was validated in clinical patient samples. We further investigated heterogeneity by moving from bulk cellular studies to single-cell analysis. The single-cell view further revealed that two driving forces from both cell-state interconversions and phenotype-specific drug selection control the cell-state transition dynamics. The single-cell studies also pinpointed the signaling network hub, RelA, as the driver molecule of the initiation of the adaptive transition. These two competing driving forces were further quantitatively modeled via a thermodynamic-inspired surprisal analysis and a modified Fokker-Planck-type kinetic model. Finally, using integrated single-cell proteomic and metabolic technology I developed to characterize the early-stage signaling and metabolic changes upon initial drug responses, we further identified two distinct paths connecting drug-sensitive and drug-tolerant states. Melanoma cells exclusively traverse one of the two paths depending on the level of MITF in the drug-naïve cells. The two trajectories are associated with distinct signaling and metabolic susceptibilities and are independently druggable. In total, this thesis combines and synergizes various physical science and systems biology approaches together with several unique single-cell technologies and analysis to obtain a deep and comprehensive understanding of non-genetic drug resistance in cancer. The findings from this thesis provide several novel insights into the rational design of effective combination therapy for overcoming the development of resistance in response to cancer treatments.</p

On systematic approaches for interpreted information transfer of inspection data from bridge models to structural analysis

In conjunction with the improved methods of monitoring damage and degradation processes, the interest in reliability assessment of reinforced concrete bridges is increasing in recent years. Automated imagebased inspections of the structural surface provide valuable data to extract quantitative information about deteriorations, such as crack patterns. However, the knowledge gain results from processing this information in a structural context, i.e. relating the damage artifacts to building components. This way, transformation to structural analysis is enabled. This approach sets two further requirements: availability of structural bridge information and a standardized storage for interoperability with subsequent analysis tools. Since the involved large datasets are only efficiently processed in an automated manner, the implementation of the complete workflow from damage and building data to structural analysis is targeted in this work. First, domain concepts are derived from the back-end tasks: structural analysis, damage modeling, and life-cycle assessment. The common interoperability format, the Industry Foundation Class (IFC), and processes in these domains are further assessed. The need for usercontrolled interpretation steps is identified and the developed prototype thus allows interaction at subsequent model stages. The latter has the advantage that interpretation steps can be individually separated into either a structural analysis or a damage information model or a combination of both. This approach to damage information processing from the perspective of structural analysis is then validated in different case studies