Dynamical Modeling Techniques for Biological Time Series Data

Doctoral thesis (2019)

The present thesis is articulated over two main topics which have in common the modeling of the dynamical properties of complex biological systems from large-scale time-series data. On one hand, this ... [more ▼]

The present thesis is articulated over two main topics which have in common the modeling of the dynamical properties of complex biological systems from large-scale time-series data. On one hand, this thesis analyzes the inverse problem of reconstructing Gene Regulatory Networks (GRN) from gene expression data. This first topic seeks to reverse-engineer the transcriptional regulatory mechanisms involved in few biological systems of interest, vital to understand the specificities of their different responses. In the light of recent mathematical developments, a novel, flexible and interpretable modeling strategy is proposed to reconstruct the dynamical dependencies between genes from short-time series data. In addition, experimental trade-offs and optimal modeling strategies are investigated for given data availability. Consistent literature on these topics was previously surprisingly lacking. The proposed methodology is applied to the study of circadian rhythms, which consists in complex GRN driving most of daily biological activity across many species. On the other hand, this manuscript covers the characterization of dynamically differentiable brain states in Zebrafish in the context of epilepsy and epileptogenesis. Zebrafish larvae represent a valuable animal model for the study of epilepsy due to both their genetic and dynamical resemblance with humans. The fundamental premise of this research is the early apparition of subtle functional changes preceding the clinical symptoms of seizures. More generally, this idea, based on bifurcation theory, can be described by a progressive loss of resilience of the brain and ultimately, its transition from a healthy state to another characterizing the disease. First, the morphological signatures of seizures generated by distinct pathological mechanisms are investigated. For this purpose, a range of mathematical biomarkers that characterizes relevant dynamical aspects of the neurophysiological signals are considered. Such mathematical markers are later used to address the subtle manifestations of early epileptogenic activity. Finally, the feasibility of a probabilistic prediction model that indicates the susceptibility of seizure emergence over time is investigated. The existence of alternative stable system states and their sudden and dramatic changes have notably been observed in a wide range of complex systems such as in ecosystems, climate or financial markets. [less ▲]

Dynamical structure function identifiability conditions enabling signal structure reconstruction

in The proceedings of the 51st IEEE Conference on Decision and Control (CDC) (2012, December)

Networks of controlled dynamical systems exhibit a variety of interconnection patterns that could be interpreted as the structure of the system. One such interpretation of system structure is a system's ... [more ▼]

Networks of controlled dynamical systems exhibit a variety of interconnection patterns that could be interpreted as the structure of the system. One such interpretation of system structure is a system's signal structure, characterized as the open-loop causal dependencies among manifest variables and represented by its dynamical structure function. Although this notion of structure is among the weakest available, previous work has shown that if no a priori structural information is known about the system, not even the Boolean structure of the dynamical structure function is identifiable. Consequently, one method previously suggested for obtaining the necessary a priori structural information is to leverage knowledge about target specificity of the controlled inputs. This work extends these results to demonstrate precisely the a priori structural information that is both necessary and sufficient to reconstruct the network from input-output data. This extension is important because it significantly broadens the applicability of the identifiability conditions, enabling the design of network reconstruction experiments that were previously impossible due to practical constraints on the types of actuation mechanisms available to the engineer or scientist. The work is motivated by the proteomics problem of reconstructing the Per-Arnt-Sim Kinase pathway used in the metabolism of sugars. [less ▲]

The Dynamics of Heat Shock Response Induced by Ultr asound Therapeutic Treatment

in Awrejcewicz, J.; Kaźmierczak, M.; Mrozowski, J. (Eds.) et al 10th Conference on Dynamical Systems – Theory and Applications, DSTA-2009 (2009)

DyPS: Dynamic, Private and Secure GWAS (Summary) - GenoPri'21 Talk

Presentation (2021, September 22)

Genome-Wide Association Studies (GWAS) identify the genomic variations that are statistically associated with a particular phenotype (e.g., a disease). GWAS results, i.e., statistics, benefit research and ... [more ▼]

Genome-Wide Association Studies (GWAS) identify the genomic variations that are statistically associated with a particular phenotype (e.g., a disease). GWAS results, i.e., statistics, benefit research and personalized medicine. The confidence in GWAS increases with the number of genomesanalyzed, which encourages federated computations where biocenters periodically include newly sequenced genomes. However, for legal and economical reasons, this collaboration can only happen if a release of GWAS results never jeopardizes the genomic privacy of data donors, if biocenters retain ownership and cannot learn each others’ data. Furthermore, given the reduced cost of sequencing DNA nowadays, there is now a need to update GWAS results in a dynamic manner, while enabling donors to withdraw consent at any time. Therefore, two challenges need to be simultaneously addressed to enable federated and dynamic GWAS: (i) the computation of GWAS statistics must rely on secure and privacy-preserving methods; and (ii) GWAS results that are publicly released should not allow any form of privacy attack. In this talk, we will introduce the problem we consider in more detail and present DyPS, the framework we have designed and recently presented at the Privacy Enhancing Technologies Symposium (PETS). We refer the reader to the full paper1 for the details we cannot cover in this short version. [less ▲]

EARLY FLOWERING4 Recruitment of EARLY FLOWERING3 in the Nucleus Sustains the Arabidopsis Circadian Clock

in Plant Cell (2012), 24(2), 428-443

The plant circadian clock is proposed to be a network of several interconnected feedback loops, and loss of any component leads to changes in oscillator speed. We previously reported that Arabidopsis ... [more ▼]

The plant circadian clock is proposed to be a network of several interconnected feedback loops, and loss of any component leads to changes in oscillator speed. We previously reported that Arabidopsis thaliana EARLY FLOWERING4 (ELF4) is required to sustain this oscillator and that the elf4 mutant is arrhythmic. This phenotype is shared with both elf3 and lux. Here, we show that overexpression of either ELF3 or LUX ARRHYTHMO (LUX) complements the elf4 mutant phenotype. Furthermore, ELF4 causes ELF3 to form foci in the nucleus. We used expression data to direct a mathematical position of ELF3 in the clock network. This revealed direct effects on the morning clock gene PRR9, and we determined association of ELF3 to a conserved region of the PRR9 promoter. A cis-element in this region was suggestive of ELF3 recruitment by the transcription factor LUX, consistent with both ELF3 and LUX acting genetically downstream of ELF4. Taken together, using integrated approaches, we identified ELF4/ELF3 together with LUX to be pivotal for sustenance of plant circadian rhythms. [less ▲]

eCoBus: Smart and sustainable public transport in Luxembourg

Scientific Conference (2020, November)

Economies of scale in recoverable robust maintenance location routing for rolling stock

in Transportation Research. Part B, Methodological (2018), 117

We consider the problem of locating maintenance facilities in a railway setting. Different facility sizes can be chosen for each candidate location and for each size there is an associated annual facility ... [more ▼]

We consider the problem of locating maintenance facilities in a railway setting. Different facility sizes can be chosen for each candidate location and for each size there is an associated annual facility costs that can capture economies of scale in facility size. Because of the strategic nature of facility location, the opened facilities should be able to handle the current maintenance demand, but also the demand for any of the scenarios that can occur in the future. These scenarios capture changes such as changes to the line plan and the introduction of new rolling stock types. We allow recovery in the form of opening additional facilities, closing facilities, and increasing the facility size for each scenario. We provide a two-stage robust programming formulation. In the first-stage, we decide where to open what size of facility. In the second-stage, we solve a NP-hard maintenance location routing problem. We reformulate the problem as a mixed integer program that can be used to make an efficient column-and-constraint generation algorithm. To show that our algorithm works on practical sized instances, and to gain managerial insights, we perform a case study with instances from the Netherlands Railways. A counter intuitive insight is that economies of scale only play a limited role and that it is more important to reduce the transportation cost by building many small facilities, rather than a few large ones to profit from economies of scale. [less ▲]

Effect of Red Blood Cell Aging In Vivo on Their Aggregation Properties In Vitro: Measurements with Laser Tweezers

in Applied Sciences (2020), 10(21), 7581-10

Red blood cell (RBC) aggregation highly influences hemorheology and blood microcirculation in the human body. The aggregation properties of RBCs can vary due to numerous factors, including RBC age. The ... [more ▼]

Red blood cell (RBC) aggregation highly influences hemorheology and blood microcirculation in the human body. The aggregation properties of RBCs can vary due to numerous factors, including RBC age. The aim of this work was to estimate in vitro the differences in the RBC aggregation properties of different RBC age populations in single-cell experiments using laser tweezers. RBCs from five healthy volunteers were separated into four subpopulations by Percoll density gradient centrifugation. Each subpopulation of the RBC was separately resuspended in autologous plasma or dextran 70 kDa (50 mg/mL). The aggregation force between the single cells was measured with holographic laser tweezers. The obtained data demonstrated an enhancement of RBC aggregation force in doublets with age: the older the cells, the higher the aggregation force. The obtained data revealed the differences between the aggregation and aggregability of RBC in dependence of the RBC in vivo age. [less ▲]

The effect of workplace relocation on individuals’ activity travel behavior

in Journal of Transport and Land Use (2018), 11(1),

On working days, homes and workplaces can be seen as anchor locations at the heart of daily mobility patterns, as well as being central to an employee’s activity pattern. In this study, we investigate how ... [more ▼]

On working days, homes and workplaces can be seen as anchor locations at the heart of daily mobility patterns, as well as being central to an employee’s activity pattern. In this study, we investigate how workplace relocation affects the entire daily activity-travel chain. While past research has shown that workplace decentralization is often associated with higher car use for the commuting trip, little is known about the effect on the whole activity travel pattern. Two waves of a two-week travel diary were completed by 43 employees of the University of Luxembourg: one before and one after the relocation of their office. Using descriptive statistics as well as standard deviational ellipses (SDE) theory combined with the results of a clustering analysis showed that workers’ activity spaces (represented by the standard deviational ellipses) were significantly modified due to the relocation of a single anchor activity location, i.e., their workplace. [less ▲]

Effectiveness of the Two-Step Dynamic Demand Estimation model on large networks

in Proceedings of 2017 5th IEEE International Conference on Models and Technologies for Intelligent Transportation Systems (MT-ITS) (2017, June 28)

In this paper, the authors present a Two-Step approach that sequentially adjusts generation and distribution values of the (dynamic) OD matrix. While the proposed methodology already provided excellent ... [more ▼]

In this paper, the authors present a Two-Step approach that sequentially adjusts generation and distribution values of the (dynamic) OD matrix. While the proposed methodology already provided excellent results for updating demand flows on a motorway, the aim of this paper is to validate this conclusion on a real network: Luxembourg City. This network represents the typical middle-sized European city in terms of network dimension. Moreover, Luxembourg City has the typical structure of a metropolitan area, composed of a city centre, ring, and suburb areas. An innovative element of this paper is to use mobile network data to create a time-dependent profile of the generated demand inside and outside the ring. To support the claim that the model is ready for practical implementation, it is interfaced with PTV Visum, one of the most widely adopted software tools for traffic analysis. Results of these experiments provide a solid empirical ground in order to further develop this model and to understand if its assumptions hold for urban scenarios. [less ▲]