Enhancing Predictive Capabilities in Data-Driven Dynamical Modeling with Automatic Differentiation: Koopman and Neural ODE Approaches

Data-driven approximations of the Koopman operator are promising for predicting the time evolution of systems characterized by complex dynamics. Among these methods, the approach known as extended dynamic mode decomposition with dictionary learning (EDMD-DL) has garnered significant attention. Here we present a modification of EDMD-DL that concurrently determines both the dictionary of observables and the corresponding approximation of the Koopman operator. This innovation leverages automatic differentiation to facilitate gradient descent computations through the pseudoinverse. We also address the performance of several alternative methodologies. We assess a 'pure' Koopman approach, which involves the direct time-integration of a linear, high-dimensional system governing the dynamics within the space of observables. Additionally, we explore a modified approach where the system alternates between spaces of states and observables at each time step -- this approach no longer satisfies the linearity of the true Koopman operator representation. For further comparisons, we also apply a state space approach (neural ODEs). We consider systems encompassing two and three-dimensional ordinary differential equation systems featuring steady, oscillatory, and chaotic attractors, as well as partial differential equations exhibiting increasingly complex and intricate behaviors. Our framework significantly outperforms EDMD-DL. Furthermore, the state space approach offers superior performance compared to the 'pure' Koopman approach where the entire time evolution occurs in the space of observables. When the temporal evolution of the Koopman approach alternates between states and observables at each time step, however, its predictions become comparable to those of the state space approach

On the laminar solutions and stability of accelerating and decelerating channel flows

We study the effect of acceleration and deceleration on the stability of channel flows. To do so, we derive an exact solution for laminar profiles of channel flows with arbitrary, time-varying wall motion and pressure gradient. This solution then allows us to investigate the stability of any unsteady channel flow. In particular, we investigate the nonnormal growth of perturbations in flows with exponentially decaying acceleration and deceleration, with comparisons to growth in a constant flow (i.e., the time-invariant simple shear or parabolic profile). We apply this acceleration and deceleration through the velocity of the walls and through the flow rate. For accelerating flows, disturbances never grow larger than disturbances in a constant flow, while decelerating flows show massive amplification of disturbances -- at a Reynolds number of 800, disturbances in the decelerating flow grow $\mathscr{O}(10^4)$ times larger than disturbances grow in a constant flow. This amplification increases as we raise the rate of deceleration and the Reynolds number. We find that this amplification arises due to a transition from spanwise perturbations leading to the largest amplification, to streamwise perturbations leading to the largest amplification that only occurs in the decelerating flow. By evolving the optimal perturbations through the linearized equations of motion, we reveal that the decelerating case achieves this massive amplification through a down-gradient Reynolds stress mechanism, which accelerating and constant flows cannot maintain. Finally, we end the paper by validating that these perturbations exhibit the same growth behaviors in direct numerical simulations

Information gain in sociotechnical systems

International audienceCommunication issues persist in sociotechnical systems with functioning communication equipment, prompting researchers and practitioners alike to bemoan the absence of information sharing. Computer scientists envision a broadly accessible virtual display, but lack the principles for selecting, formatting and organizing content to make it useful. We argue that what is needed is information rather than data, and that situating data in context is key to the provision of information. Documentation of information exchange issues in real crisis management is quite superficial, generally pointing to conclusions without any supporting data. Using documentation of the Deepwater Horizon Accident in 2010, we suggest three requirements for the design of computationally supported information exchange: 1) computational support to distribute distilled information, not low-level data, 2) a computationally accessible, current plan to provide context to guide the routing of information to interested parties and 3) a means to detect and elevate newly relevant, but formerly suppressed detail

Cross metathesis for the synthesis of HDAC inhibitors. Potential in multitarget drug design

Histone deacetylases represent a family of eleven zinc-dependant enzymes. Their over expression has been correlated to several human diseases, in particular cancers. The search for compounds able to selectively inhibit one of these HDAC is of high importance to obtain less side effect during treatment as well as avoiding of target effects. In this work we have designed a series of inhibitors using an asymmetric cross metathesis approach. We present the synthesis, some molecular modelling and the biological activities of the prepared compounds.Link ka Knjizi sažetaka se nalazi ovde - http://www.mutalig.eu/2017/06/2nd-annual-meeting-porto-september-21-24-2017

Development of cross metathesis for the design of HDAC inhibitors

Epigenetic histones post translational modifications are key players in the regulation of gene expression. Amongst all possible modifications, the N-acetylation of the lysine side chains located at the N-terminal tail of histones is involved in the relaxation of chromatine and contributes to gene transcription. This acetylation status is controlled by histone acetyl transferases (HAT) and histone deacetylases (HDAC and SIRT). The abnormal expression of HDAC has been linked to the progression of several human diseases such as cancers. Therefore, the development of HDAC inhibitors has emerged as a valuable therapeutic strategy, with currently four compounds approved by the FDA and a fifth one in China. Recent data suggested that combination therapies with HDAC inhibitors may contribute to better clinical results. HDACs are zinc-dependant enzymes grouped in a family of 11 proteins (HDAC1-11), grouped in three classes: class I (HDAC1-3,8), class Il (HDAC4-7,9,10) and class IV (HDAC11). The fourth group of deacetylases contains the class Ill NADH+-dependent sirtuins (SIRT1-7). The standard pharmacophore for HDAC inhibitors involves a zinc-binding group (ZBG) linked through a spacer to a “cap” group in interaction with the external solvent accessible surface. We were interested in alternative chemistries to access HDAC inhibitors in which the intermediate spacer could be build out of two similar building blocks, one bearing the ZBG and on bearing the cap group. By selecting linear alkyl-based spacer, cross metathesis appeared to be a short and flexible strategy, provided it supports the presence of highly oxophile functional groups such as carbonyl groups. This poster summarizes our findings in the application of cross metathesis and the biological evaluations of some of the compounds obtained

BRAF Mutations in Advanced Cancers: Clinical Characteristics and Outcomes

BACKGROUND: Oncogenic BRAF mutations have been found in diverse malignancies and activate RAF/MEK/ERK signaling, a critical pathway of tumorigenesis. We examined the clinical characteristics and outcomes of patients with mutant (mut) BRAF advanced cancer referred to phase 1 clinic. METHODS: We reviewed the records of 80 consecutive patients with mutBRAF advanced malignancies and 149 with wild-type (wt) BRAF (matched by tumor type) referred to the Clinical Center for Targeted Therapy and analyzed their outcome. RESULTS: Of 80 patients with mutBRAF advanced cancer, 56 had melanoma, 10 colorectal, 11 papillary thyroid, 2 ovarian and 1 esophageal cancer. Mutations in codon 600 were found in 77 patients (62, V600E; 13, V600K; 1, V600R; 1, unreported). Multivariate analysis showed less soft tissue (Odds ratio (OR) = 0.39, 95%CI: 0.20-0.77, P = 0.007), lung (OR = 0.38, 95%CI: 0.19-0.73, p = 0.004) and retroperitoneal metastases (OR = 0.34, 95%CI: 0.13-0.86, p = 0.024) and more brain metastases (OR = 2.05, 95%CI: 1.02-4.11, P = 0.043) in patients with mutBRAF versus wtBRAF. Comparing to the corresponding wtBRAF, mutBRAF melanoma patients had insignificant trend to longer median survival from diagnosis (131 vs. 78 months, p = 0.14), while mutBRAF colorectal cancer patients had an insignificant trend to shorter median survival from diagnosis (48 vs. 53 months, p = 0.22). In melanoma, V600K mutations in comparison to other BRAF mutations were associated with more frequent brain (75% vs. 36.3%, p = 0.02) and lung metastases (91.6% vs. 47.7%, p = 0.007), and shorter time from diagnosis to metastasis and to death (19 vs. 53 months, p = 0.046 and 78 vs. 322 months, p = 0.024 respectively). Treatment with RAF/MEK targeting agents (Hazard ratio (HR) = 0.16, 95%CI: 0.03-0.89, p = 0.037) and any decrease in tumor size after referral (HR = 0.07, 95%CI: 0.015-0.35, p = 0.001) correlated with longer survival in mutBRAF patients. CONCLUSIONS: BRAF appears to be a druggable mutation that also defines subgroups of patients with phenotypic overlap, albeit with differences that correlate with histology or site of mutation

La propriété privée à l'épreuve de l'intérêt général : étude de la place de la propriété privée dans la crise du logement en France

Ce mémoire s'attachera à montrer la place particulière de la propriété privée dans la crise du logement, aussi bien dans ses mécanismes économiques que dans ses conséquences sociales, tout en explorant les rapports qu'elle a entretenus avec l'intérêt général. En matière de logement, l'intérêt général peut se définir comme la nécessité d'assurer l'équilibre entre le domaine économique du logement et sa dimension sociale, afin que l'un ne s'exerce pas au détriment de l'autre. L'objectif est de garantir un secteur économique performant créateur d'emplois dans la construction et de revenus dans la location, tout en permettant à chacun d'avoir un logement. Dans un contexte de crise du logement où l'intérêt économique se développe au détriment de la dimension sociale, l'intérêt général impose théoriquement à l'État une action pour préserver les aspects sociaux et, par conséquent, une restriction des intérêts particuliers au profit de l'intérêt général. Nous tenterons donc de déterminer dans quelle mesure les pouvoirs publics ont eu le souci de l'intérêt général et se sont employés à défendre l'intérêt social face à l'intérêt économique. Mais nous étudierons surtout comment la propriété privée s'est comportée dans ce contexte de crise par rapport à cet impératif théorique d'intérêt général, et ce, indépendamment du choix des pouvoirs publics. Notre mémoire s'organisera de la façon suivante : nous commencerons par étudier attentivement l'évolution de la propriété privée du logement en France, notamment en regard de la montée du droit au logement ; nous étudierons ensuite le rôle de la propriété dans la "création" des différentes composantes immobilières de la crise du logement, ainsi que sur ses conséquences sociales ; enfin, nous terminerons par une interrogation sur une possible convergence entre propriété privée et intérêt général en matière de logement en France, au regard d'initiatives étrangères et de l'évolution des systèmes juridiques internationaux

Improvement of the effectiveness of chemotherapeutic agents used in the treatment of thoracic cancers : combinations or vectorization

L’adenocarcinome pulmonaire (ADCA) et le mesotheliome pleural malin (MPM) sont deux cancers thoraciques agressifs pour lesquels les traitements conventionnels manquent d’efficacite. Il est donc necessaire de proposer de nouvelles strategies anti-cancereuses. L’objectif de mon travail a donc consiste a explorer deux voies d’amelioration de therapies anti-tumorales. La premiere approche visait a ameliorer les effets therapeutiques d’analogues de nucleosides utilises en clinique, la Decitabine (5-AZA), un agent hypomethylants, et la Gemcitabine. Ces deux drogues possedent une voie de metabolisation commune mettant en oeuvre la cytidine deaminase (CDA). Ainsi, j’ai combine avec ces deux agents un inhibiteur de cette enzyme pour augmenter les effets anti-tumoraux de la Decitabine et de la Gemcitabine pour traiter l’ADCA. La seconde approche s’interessait a l’amelioration des proprietes pharmacocinetiques d’agents therapeutiques couramment utilises. Pour cela, nous avons developpe, en collaboration avec l’equipe du Pr. Elena Ishow (CEISAM, Nantes), des nanovecteurs aux proprietes theranostiques, c’est a dire therapeutique et diagnostique grace a l’introduction de proprietes magnetiques exploitables pour l’imagerie de resonance magnetique (IRM). Les systemes nanometriques nus ont ete caracterises in vitro et in vivo dans un modele de MPM et enfin nous avons choisi de vectoriser un agent antitumoral bien connu et deja utilise en clinique, la Doxorubicine.Lung adenocarcinoma (ADCA) and malignant pleural mesothelioma (MPM) are two aggressive thoracic cancers for which current treatments are poorly efficient. Therefore, it’s necessary to propose new anti-cancer strategies. The objective of my work was to explore two approaches to improve anti-tumor therapies. The first approach was to improve therapeutic effects of nucleoside analogues used in clinic, Decitabine (5-AZA), a hypomethylating agent, or Gemcitabine. These two drugs have a common metabolic pathway implicating the enzyme cytidine deaminase (CDA). Thus, I combined these drugs with an inhibitor of this enzyme to increase antitumor effects of Decitabine and Gemcitabine to treat ADCA. The second approach develop during my PhD was focused on the improvement of pharmacokinetic properties of currently used therapeutic agents. In collaboration with Pr. Elena Ishow (CEISAM, Nantes), we developed a nanovector with theranostic properties, that is therapeutic and diagnostic thanks to addition of magnetic properties useful for magnetic resonance imagery (RMI). Bare nanoscale systems were characterized in vitro and in vivo in a model of MPM and finally we chose to vectorize a well-known antitumor agent already used in clinic, Doxorubicin