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With advances in high-throughput techniques, the availability of large-scale omics data has revolutionized the fields of medicine and biology, and has offered a better understanding of the underlying biological mechanisms. However, the high-dimensionality and the unknown association structure between different data types make statistical integration analyses challenging. In this dissertation, we develop three dimensionality reduction methods to detect nonlinear association structure using omics data. First, we propose a method for variable selection in a nonparametric additive quantile regression framework. We enforce a network regularization to incorporate information encoded by known networks. To account for nonlinear associations, we approximate the additive functional effect of each predictor with the expansion of a B-spline basis. We implement the group Lasso penalty to achieve sparsity. We define the network-constrained penalty by regulating the difference between the effect functions of any two linked genes (predictors) in the network. Simulation studies show that our proposed method performs well in identifying truly associated genes with fewer falsely associated genes than alternative approaches. Second, we develop a canonical correlation analysis (CCA)-based method, canonical distance correlation analysis (CDCA), and leverage the distance correlation to capture the overall association between two sets of variables. The CDCA allows untangling linear and nonlinear dependence structures. Third, we develop the sparse CDCA (sCDCA) method to achieve sparsity and improve result interpretability by adding penalties on the loadings from the CDCA. The sCDCA method can be applied to data with large dimensionality and small sample size. We develop iterative majorization-minimization-based coordinate descent algorithms to compute the loadings in the CDCA and sCDCA methods. Simulation studies show that the proposed CDCA and sCDCA approaches have better performance than classical CCA and sparse CCA (sCCA) in nonlinear settings and have similar performance in linear association settings. We apply the proposed methods to the Framingham Heart Study (FHS) to identify body mass index associated genes, the association structure between metabolic disorders and metabolite profiles, and a subset of metabolites and their associated type 2 diabetes (T2D)-related genes. / 2023-11-05T00:00:00Z

Durant cette thèse, nous avons abordé l'étude de la réactivité en phase gazeuse des biomolécules. L’avènement des techniques d’ionisation douces telle que l’ionisation par éléctronébulisation, a rendu possible ces dernières années, la formation d'ions en phase gazeuse sans dégrader la biomolécule étudiée.La Dissociation Induite par Collision (CID) est un cas particulier de spectrométrie de masse en tandem, que nous avons utilisée durant ce travail. Le principe du CID est d'activer les modes rovibrationnelles d’un système moléculaire ionique par collision avec un gaz inerte, ce qui augmente la probabilité de fragmentation de l'ion. Bien qu'étant une technique très utile d'un point de vue analytique, la spectrométrie de masse en tandem ne donne pas d'informations sur les mécanismes des réactions se produisant dans la cellule de collision; afin d’obtenir ces informations, les simulations de dynamique chimiques apparaissent comme un outil satisfaisant. En effet, en utilisant la dynamique directe, nous évitons ainsi d'explorer la totalité de la surface d'énergie potentielle, qui devient compliquée lors de l’étude d’édifices moléculaires de grande taille. Etant donné que les simulations de dynamique chimiques sont limitées à de courtes échelles, de l’ordre de la dizaine de picosecondes, nous avons également employé la théorie unimoléculaire RRKM (Rice-Ramsperger-Kassel-Marcus) pour étudier la réactivité à des temps plus longs, en vue de comprendre les processus réactionnels se produisant à l’issue du processus de relaxation vibrationnelle intramoléculaire (IVR). Durant ce travail de thèse, nous avons choisi d'étudier comme système modèle de base nucléique la molécule d'uracile. Par ailleurs,nous avons aussi étudié la réactivité en phase gazeuse de sucres (cellobiose, maltose et gentiobiose), qui ont été au préalable dérivatisés afin de localiser la charge sur la molécule et ainsi simplifier l’étude théorique associée. / In the present thesis, we address the study of the reactivity of biomolecules in the gasphase.The advent of soft ionization techniques such as electrospray ionization, made possible, in the last years, the gentle formation of ions in the gas phase without breaking the molecule understudy.Collision Induced Dissociation (CID) is aparticular case of tandem mass spectrometrydynamics simulations are pointed like asatisfactory tool. Using direct dynamics weavoid exploring the whole potential energysurface, which becomes really complicatedwhen dealing with big molecules.Since chemical dynamics simulations arerestricted to the short time scale reactivity,typically ~10ps, we make use of the Rice–Ramsperger–Kassel–Marcus (RRKM)unimolecular theory to study the reactivity atUniversité Paris-SaclayEspace Technologique / Immeuble DiscoveryRoute de l’Orme aux Merisiers RD 128 / 91190 Saint-Aubin, Francethat we use in the present thesis. The aim of CIDis to activate the rovibrational modes of an ionicmolecular system by collisions with an inert gas,increasing the probability of the ion of beingfragmented.Despite being a really useful technique, tandemmass spectrometry does not give informationabout the mechanisms of the reactions takingplace in the collision cell; in order to obtain suchinformation, chemicallonger time scales to understand reaction pathsthat take place after intramolecular vibrationrelaxation (IVR).In the present thesis we have chosen to study asmodel system of nucleobase the uracil molecule.Furthermore, we also studied the gas-phase reactivity of carbohydrates (cellobiose, maltose and gentiobiose), which were preliminarily derivatized in order to simplify the charge localization, and consequently the theoretical study.

京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第19521号 / 理博第4181号 / 新制||理||1600(附属図書館) / 32557 / 京都大学大学院理学研究科化学専攻 / (主査)教授 林 重彦, 教授 谷村 吉隆, 教授 松本 吉泰 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

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A new class of Planar Ultrawideband Modular Antenna (PUMA) arrays, termed PUMAv3, is introduced to offer improved performance and further meet demand needs for multifunctional systems. PUMAv3 extends the frequency scalability of PUMA arrays to mm-waves (approximately 50 GHz) and improves bandwidth by 50\% without the use of a matching network or external baluns. The major enabling technical innovation is the advent of a new common-mode mitigation mechanism that relies upon capacitively-loaded shorting vias to push broadside catastrophic resonances below the operating band without inhibiting low-end bandwidth performance. Ridged waveguide models are employed to explain the operational principles and accurately predict the location of the common-mode frequency within the new array topology. Additionally, the superstrate loading scheme is split into two exclusive layers to enhance broadside and wide angle impedance levels while maintaining the highest frequency at 97% of the grating lobe frequency and reducing the overall array profile by up to 30%. The PUMAv3 also retains the attractive practical advantages inherent to the PUMA array family: aperture modularity, direct 50-ohm feeding, and low-cost planar multilayer PCB fabrication. Infinite array full-wave simulations of a dual-polarized PUMAv3 satisfying manufacture guidelines suggest 10.6-47.6 GHz (4.5:1) operation with strong VSWR levels out to 45 degrees, high port isolation and low cross-polarization.

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In this work, the development of parameters for a series of imidazolium-based ionic liquids molecules, now included in the AMOEBA force field, is discussed. The quality of obtained parameters is tested in a variety of calculations to reproduce structural, thermodynamic, and transport properties. First, it is proposed a novel method to parameterize in a faster, and more efficient way parameters for the AMOEBA force field that can be applied to any imidazolim-based cation. Second, AMOEBA-IL polarizable force field is applied to study the N-tert-butyloxycarbonylation of aniline reaction mechanism in water/[EMIM][BF4] solvent via QM/MM approach and compared with the reaction carried out in gas-phase and implicit solvent media. Third, AMOEBA-IL force field is applied in alchemical calculations. Free energies of solvation for selected solutes solvated in [EMIm][OTf] are calculated via BAR method implemented in TINKER considering the effect of polarization as well as the methodology to perform the sampling of the alchemical process. Finally, QM/MM calculations using AMOEBA to get more insights into the catalytic reaction mechanism of horseradish peroxidase enzyme, particularly the structures involved in the transition from Cp I to Cp II.