Trajectory probability hypothesis density filter

This paper presents the probability hypothesis density (PHD) filter for sets of trajectories: the trajectory probability density (TPHD) filter. The TPHD filter is capable of estimating trajectories in a principled way without requiring to evaluate all measurement-to-target association hypotheses. The TPHD filter is based on recursively obtaining the best Poisson approximation to the multitrajectory filtering density in the sense of minimising the Kullback-Leibler divergence. We also propose a Gaussian mixture implementation of the TPHD recursion. Finally, we include simulation results to show the performance of the proposed algorithm

Optimisation of flow chemistry: tools and algorithms

The coupling of flow chemistry with automated laboratory equipment has become increasingly common and used to support the efficient manufacturing of chemicals. A variety of reactors and analytical techniques have been used in such configurations for investigating and optimising the processing conditions of different reactions. However, the integrated reactors used thus far have been constrained to single phase mixing, greatly limiting the scope of reactions for such studies. This thesis presents the development and integration of a millilitre-scale CSTR, the fReactor, that is able to process multiphase flows, thus broadening the range of reactions susceptible of being investigated in this way. Following a thorough review of the literature covering the uses of flow chemistry and lab-scale reactor technology, insights on the design of a temperature-controlled version of the fReactor with an accuracy of ±0.3 ºC capable of cutting waiting times 44% when compared to the previous reactor are given. A demonstration of its use is provided for which the product of a multiphasic reaction is analysed automatically under different reaction conditions according to a sampling plan. Metamodeling and cross-validation techniques are applied to these results, where single and multi-objective optimisations are carried out over the response surface models of different metrics to illustrate different trade-offs between them. The use of such techniques allowed reducing the error incurred by the common least squares polynomial fitting by over 12%. Additionally, a demonstration of the fReactor as a tool for synchrotron X-Ray Diffraction is also carried out by means of successfully assessing the change in polymorph caused by solvent switching, this being the first synchrotron experiment using this sort of device. The remainder of the thesis focuses on applying the same metamodeling and cross-validation techniques used previously, in the optimisation of the design of a miniaturised continuous oscillatory baffled reactor. However, rather than using these techniques with physical experimentation, they are used in conjunction with computational fluid dynamics. This reactor shows a better residence time distribution than its CSTR counterparts. Notably, the effect of the introduction of baffle offsetting in a plate design of the reactor is identified as a key parameter in giving a narrow residence time distribution and good mixing. Under this configuration it is possible to reduce the RTD variance by 45% and increase the mixing efficiency by 60% when compared to the best performing opposing baffles geometry

Heterogeneously catalysed aerobic oxidation of alcohols in microstructured reactors

The goal of this thesis research was to develop microfluidic platforms for the study of gas-solid and gas-liquid-solid alcohol oxidation reactions. The desired products of these reactions are of great importance industrially due to their value as intermediates in industries such as the fine chemical and pharmaceutical sectors. The application of microreaction technology to these reactions is proving to be beneficial due to their high surface area-to-volume ratio, resulting in fast heat and mass transfer and an ability to circumvent problems such as high exothermicity, mass transfer limitations, and poor control of reaction conditions. Two types of reaction systems were developed to facilitate this research; a three-phase micro-packed bed reactor for the study of benzyl alcohol oxidation on supported gold-palladium catalyst and a wall-coated microreactor for the study of methanol oxidation to formaldehyde on silver catalyst. Reaction and deactivation flow studies were first conducted in continuous flow microfluidic setups to understand catalyst activation and deactivation behaviour, culminating in the selection of the most stable catalyst formulation. These reaction studies were followed by a series of hydrodynamic and mass transfer investigations, where differences in hydrodynamics to conventional macroscale systems were identified, and a classification of flow regimes applicable to micro-packed bed reactors presented. An understanding of the influence of hydrodynamics on mass transfer, catalyst deactivation and reaction performance has been developed for benzyl alcohol oxidation, resulting in enhancement in flow reactor performance in comparison to batch. Exploration of different microreactor designs, to cope with challenging process conditions, as well as the application of novel methods for reactor characterization (such as Raman spectroscopy) are also presented

Aeronautical engineering: A continuing bibliography with indexes (supplement 119)

This bibliography lists 341 reports, articles, and other documents introduced into the NASA scientific and technical information system in January 1980. Abstracts on the engineering and theoretical aspects of design, construction, evaluation, testing, operation, and performance of aircraft (including aircraft engines) and associated components, equipment, and systems are presented. Research and development in aerodynamics, aeronautics, and ground support equipment for aeronautical vehicles are also presented

System of Systems Engineering for Policy Design

A system of systems (SoS) framework is proposed for policy design that takes into account the value systems of multiple participants, harnesses the complexity of strategic interactions among participants, and confronts the risks and uncertainties present in participants’ decision making. SoS thinking provides an integrative and adaptive mindset, which is needed to tackle policy challenges characterized by conflict, complexity, and uncertainty. With the aim of putting SoS thinking into practice, operational methods and tools are presented herein. Specifically, SoS engineering methodologies to create value system models, agent-based models of competitive and cooperative behaviour under conflict, and risk management models are developed and integrated into the framework. The proposed structure, methods and tools can be utilized to organize policy design discourse. Communication among participants involved in the policy discussion is structured around SoS models, which are used to integrate multiple perspectives of a system and to test the effectiveness of policies in achieving desirable outcomes under varying conditions. In order to demonstrate the proposed methods and tools that have been developed to enliven policy design discourse, a theoretical common-pool resources dilemma is utilized. The generic application illustrates the methodology of constructing ordinal preferences from values. Also, it is used to validate the agent-based modeling and simulation platform as a tool to investigate strategic interactions among participants and harness the potential to influence and enable participants to achieve desirable outcomes. A real-world common pool resources dilemma in the provisioning and security considerations of the Straits of Malacca and Singapore is examined and employed as a case study for applying strategic conflict models in risk management. Overall, this thesis advances the theory and application of SoS engineering and focuses on understanding value systems, handling complexity in terms of conflict dynamics, and finally, enhancing risk management

The Development of Microreactor Technology for the Study of Multistep Catalytic Systems and Rapid Kinetic Modelling

Microreactor technology was applied to the study of catalytic systems because their high rates of heat and mass transport, improved safety and ease of automation makes them particularly effective research tools in this area. A multistep flow system for the synthesis of benzylacetone from benzyl alcohol via oxidation, aldol condensation and reduction reactions was developed by utilising three micropacked bed reactors and a gas liquid membrane separator. This reaction had previously been conducted in batch cascade, however, the multistep flow system enabled the achievement of higher yields with lower catalyst contact times because separating each reaction into its own reactor allowed greater freedom to tailor the operating conditions for each reaction. The multistep system also allowed the catalysts to be studied in a process wide environment, leading to the identification of significant catalyst inhibition due to by and co-products from upstream reactions. An automated closed loop microreactor platform was developed which utilised Model-Based Design of Experiments (MBDoE) algorithms for rapid kinetic modelling of catalytic reactions. The automated platform was first applied to the homogenous esterification of benzoic acid with ethanol using a sulfuric acid catalyst, where a campaign of steady-state experiments designed by online MBDoE led to the estimation of kinetic parameters with much higher precision than a factorial campaign of experiments. This reaction was then conducted with MBDoE designed transient experiments, which dramatically reduced the experimental time required. The same reaction was studied using a heterogeneous Amberlyst-15 catalyst, and by combining factorial designs, practical identifiability tests and MBDoE for model discrimination and parameter precision, a practical kinetic model was identified in just 3 days. The automated platform was applied to the oxidation of 5-hydroxymethylfurfural in a micropacked bed reactor with gas-liquid flow using AuPd/TiO2 catalysts, however due to poor experimental reproducibility, a kinetic model was not identified

Cell-free expression and molecular modeling of the γ-secretase complex and G-protein-coupled receptors

Alzheimer’s disease (AD), which was first reported more than a century ago by Alhzeimer, is one of the commonest forms of dementia which affects >30 million people globally (>8 million in Europe). The origin and pathogenesis of AD is poorly understood and there is no cure available for the disease. AD is characterized by the accumulation of senile plaques composed of amyloid beta peptides (Ab 37-43) which is formed by the gamma secretase (GS) complex by cleaving amyloid precursor protein. Therefore GS can be an attractive drug target. Since GS processes several other substrates like Notch, CD44 and Cadherins, nonspecific inhibition of GS has many side effects. Due to the lack of crystal structure of GS, which is attributed to the extreme difficulties in purifying it, molecular modeling can be useful to understand its architecture. So far only low resolution cryoEM structures of the complex has been solved which only provides a rough structure of the complex at low 12-15 A resolution Furthermore the activity of GS in vitro can be achieved by means of cell-free (CF) expression. GS comprises catalytic subunits namely presenilins and supporting elements containing Pen-2, Aph-1 and Nicastrin. The origin of AD is hidden in the regulated intramembrnae proteolysis (RIP) which is involved in various physiological processes and also in leukemia. So far growth factors, cytokines, receptors, viral proteins, cell adhesion proteins, signal peptides and GS has been shown to undergo RIP. During RIP, the target proteins undergo extracellular shredding and intramembrane proteolysis. This thesis is based on molecular modeling, molecular dynamics (MD) simulations, cell-free (CF) expression, mass spectrometry, NMR, crystallization, activity assay etc of the components of GS complex and G-protein coupled receptors (GPCRs). First I validated the NMR structure of PS1 CTF in detergent micelles and lipid bilayers using coarse-grained MD simulations using MARTINI forcefield implemented in Gromacs. CTF was simulated in DPC micelles, DPPC and DLPC lipid bilayer. Starting from random configuration of detergent and lipids, micelle and lipid bilyer were formed respectively in presence of CTF and it was oriented properly to the micelle and bilyer during the simulation. Around DPC molecules formed micelle around CTF in agreement of the experimental results in which 80-85 DPC molecules are required to form micelles. The structure obtained in DPC was similar to that of NMR structure but differed in bilayer simulations showed the possibility of substrate docking in the conserved PAL motif. Simulations of CTF in implicit membrane (IMM1) in CHAMM yielded similar structure to that from coarse grained MD. I performed cell-free expression optimization, crystallization and NMR spectroscopy of Pen-2 in various detergent micelles. Additionally Pen-2 was modeled by a combination of rosetta membrane ab-initio method, HHPred distant homology modeling and incorporating NMR constraints. The models were validated by all atom and coarse grained MD simulations both in detergent micelles and POPC/DPPC lipid bilayers using MARTINI forcefield. GS operon consisting of all four subunits was co-expressed in CF and purified. The presence of of GS subunits after pull-down with Aph-1 was determined by western blotting (Pen-2) and mass spectrometry (Presenilin-1 and Aph-1). I also studied interactions of especially PS1 CTF, APP and NTF by docking and MD. I also made models and interfaces of Pen-2 with PS1 NTF and checked their stability by MD simulations and compared with experimental results. The goal is to model the interfaces between GS subunits using molecular modeling approaches based on available experimental data like cross-linking, mutations and NMR structure of C-terminal fragment of PS1 and transmembrane part of APP. The obtained interfaces of GS subunits may explain its catalysis mechanism which can be exploited for novel lead design. Due to lack of crystal/NMR structure of the GS subunits except the PS1 CTF, it is not possible to predict the effect of mutations in terms of APP cleavage. So I also developed a sequence based approach based on machine learning using support vector machine to predict the effect of PS1 CTF L383 mutations in terms of Aβ40/Aβ42 ratio with 88% accuracy. Mutational data derived from the Molgen database of Presenilin 1 mutations was using for training. GPCRs (also called 7TM receptors) form a large superfamily of membrane proteins, which can be activated by small molecules, lipids, hormones, peptides, light, pain, taste and smell etc. Although 50% of the drugs in market target GPCRs , only few are targeted therapeutically. Such wide range of targets is due to involvement of GPCRs in signaling pathways related to many diseases i.e. dementia (like Alzheimer's disease), metabolic (like diabetes) including endocrinological disorders, immunological including viral infections, cardiovascular, inflammatory, senses disorders, pain and cancer. Cannabinoid and adrenergic receptors belong to the class A (similar to rhodopsin) GPCRs. Docking of agonists and antagonists to CB1 and CB2 cannabinoid receptors revealed the importance of a centrally located rotamer toggle switch, and its possible role in the mechanism of agonist/antagonist recognition. The switch is composed of two residues, F3.36 and W6.48, located on opposite transmembrane helices TM3 and TM6 in the central part of the membranous domain of cannabinoid receptors. The CB1 and CB2 receptor models were constructed based on the adenosine A2A receptor template. The two best scored conformations of each receptor were used for the docking procedure. In all poses (ligand-receptor conformations) characterized by the lowest ligand-receptor intermolecular energy and free energy of binding the ligand type matched the state of the rotamer toggle switch: antagonists maintained an inactive state of the switch, whereas agonists changed it. In case of agonists of β2AR, the (R,R) and (S,S) stereoisomers of fenoterol, the molecular dynamics simulations provided evidence of different binding modes while preserving the same average position of ligands in the binding site. The (S,S) isomer was much more labile in the binding site and only one stable hydrogen bond was created. Such dynamical binding modes may also be valid for ligands of cannabinoid receptors because of the hydrophobic nature of their ligand-receptor interactions. However, only very long molecular dynamics simulations could verify the validity of such binding modes and how they affect the process of activation. Human N-formyl peptide receptors (FPRs) are G protein-coupled receptors (GPCRs) involved in many physiological processes, including host defense against bacterial infection and resolving inflammation. The three human FPRs (FPR1, FPR2 and FPR3) share significant sequence homology and perform their action via coupling to Gi protein. Activation of FPRs induces a variety of responses, which are dependent on the agonist, cell type, receptor subtype, and also species involved. FPRs are expressed mainly by phagocytic leukocytes. Together, these receptors bind a large number of structurally diverse groups of agonistic ligands, including N-formyl and nonformyl peptides of different composition, that chemoattract and activate phagocytes. For example, N-formyl-Met-Leu-Phe (fMLF), an FPR1 agonist, activates human phagocyte inflammatory responses, such as intracellular calcium mobilization, production of cytokines, generation of reactive oxygen species, and chemotaxis. This ligand can efficiently activate the major bactericidal neutrophil functions and it was one of the first characterized bacterial chemotactic peptides. Whereas fMLF is by far the most frequently used chemotactic peptide in studies of neutrophil functions, atomistic descriptions for fMLF-FPR1 binding mode are still scarce mainly because of the absence of a crystal structure of this receptor. Elucidating the binding modes may contribute to designing novel and more efficient non-peptide FPR1 drug candidates. Molecular modeling of FPR1, on the other hand, can provide an efficient way to reveal details of ligand binding and activation of the receptor. However, recent modelings of FPRs were confined only to bovine rhodopsin as a template. To locate specific ligand-receptor interactions based on a more appropriate template than rhodopsin we generated the homology models of FPR1 using the crystal structure of the chemokine receptor CXCR4, which shares over 30% sequence identity with FPR1 and is located in the same γ branch of phylogenetic tree of GPCRs (rhodopsin is located in α branch). Docking and model refinement procedures were pursued afterward. Finally, 40 ns full-atom MD simulations were conducted for the Apo form as well as for complexes of fMLF (agonist) and tBocMLF (antagonist) with FPR1 in the membrane. Based on locations of the N- and C-termini of the ligand the FPR1 extracellular pocket can be divided into two zones, namely, the anchor and activation regions. The formylated M1 residue of fMLF bound to the activation region led to a series of conformational changes of conserved residues. Internal water molecules participating in extended hydrogen bond networks were found to play a crucial role in transmitting the agonist-receptor interactions. A mechanism of initial steps of the activation concurrent with ligand binding is proposed. I accurately predicted the structure and ligand binding pose of dopamine receptor 3 (RMSD to the crystal structure: 2.13 Å) and chemokine receptor 4 (CXCR4, RMSD to the crystal structure 3.21 Å) in GPCR-Dock 2010 competition. The homology model of the dopamine receptor 3 was 8 th best overall in the competition

Machine Learning in Discrete Molecular Spaces

The past decade has seen an explosion of machine learning in chemistry. Whether it is in property prediction, synthesis, molecular design, or any other subdivision, machine learning seems poised to become an integral, if not a dominant, component of future research efforts. This extraordinary capacity rests on the interac- tion between machine learning models and the underlying chemical data landscape commonly referred to as chemical space. Chemical space has multiple incarnations, but is generally considered the space of all possible molecules. In this sense, it is one example of a molecular set: an arbitrary collection of molecules. This thesis is devoted to precisely these objects, and particularly how they interact with machine learning models. This work is predicated on the idea that by better understanding the relationship between molecular sets and the models trained on them we can improve models, achieve greater interpretability, and further break down the walls between data-driven and human-centric chemistry. The hope is that this enables the full predictive power of machine learning to be leveraged while continuing to build our understanding of chemistry. The first three chapters of this thesis introduce and reviews the necessary machine learning theory, particularly the tools that have been specially designed for chemical problems. This is followed by an extensive literature review in which the contributions of machine learning to multiple facets of chemistry over the last two decades are explored. Chapters 4-7 explore the research conducted throughout this PhD. Here we explore how we can meaningfully describe the properties of an arbitrary set of molecules through information theory; how we can determine the most informative data points in a set of molecules; how graph signal processing can be used to understand the relationship between the chosen molecular representation, the property, and the machine learning model; and finally how this approach can be brought to bear on protein space. Each of these sub-projects briefly explores the necessary mathematical theory before leveraging it to provide approaches that resolve the posed problems. We conclude with a summary of the contributions of this work and outline fruitful avenues for further exploration