The U.N. projects the world population to reach nearly 10 billion people by 2050, which will cause demand for manufactured goods to reach unforeseen levels. In order for us to produce the goods to support an equitable future, the methods in which we manufacture those goods must radically change. The emerging Circular Economy (CE) concept for production systems has promised to drastically increase economic/business value by significantly reducing the world’s resource consumption and negative environmental impacts. However, CE is inherently limited because of its emphasis on recycling and reuse of materials. CE does not address the holistic changes needed across all of the fundamental elements of manufacturing: products, processes, and systems. Therefore, a paradigm shift is required for moving from sustainment to sustainability to “produce more with less” through smart, innovative and transformative convergent manufacturing approaches rooted in redesigning next generation manufacturing infrastructure. This PhD research proposes the Helical Economy (HE) concept as a novel extension to CE. The proposed HE concepts shift the CE’s status quo paradigm away from post-use recovery for recycling and reuse and towards redesigning manufacturing infrastructure at product, process, and system levels, while leveraging IoT-enabled data infrastructures and an upskilled workforce. This research starts with the conceptual overview and a framework for implementing HE in the discrete product manufacturing domain by establishing the future state vision of the Helical Economy Manufacturing Method (HEMM). The work then analyzes two components of the framework in detail: designing next-generation products and next-generation IoT-enabled data infrastructures. The major research problems that need to be solved in these subcomponents are identified in order to make near-term progress towards the HEMM. The work then proceeds with the development and discussion of initial methods for addressing these challenges. Each method is demonstrated using an illustrative industry example. Collectively, this initial work establishes the foundational body of knowledge for the HE and the HEMM, provides implementation methods at the product and IoT-enabled data infrastructure levels, and it shows a great potential for HE’s ability to create and maximize sustainable value, optimize resource consumption, and ensure continued technological progress with significant economic growth and innovation. This research work then presents an outlook on the future work needed, as well as calls for industry to support the continued refinement and development of the HEMM through relevant prototype development and subsequent applications.

Peptidomimetics are synthetic oligomers that resemble the activities of peptides. Their advantages over peptides include high stability towards proteolysis and enormous chemical diversity. Over the past two decades, there have been extensive efforts to develop peptide mimics, such as beta-peptides, peptoids, D-peptides, etc. The research on peptidomimetics have led to many important applications in both medicinal and material science. In order to explore new functions, the discovery of peptidomimetics with novel frameworks is essential. We reported the synthesis and evaluation of a new class of peptidomimetics, termed as gamma-AApeptides. Previous studies of gamma-AApeptides have revealed that gamma-AApeptides are highly resistant to proteolysis, and are highly amendable to chemical diversification. However, new biological activities and folding properties of gamma-AApeptides still need to be explored. In order to expand the potential of gamma-AApeptides in chemical biology and medicinal chemistry, I have been focusing on the development of new methods to synthesize linear and cyclic gamma-AApeptides, development of one-bead-one-compound (OBOC) gamma-AApeptide libraries for the discovery of inhibitors against beta-amyloid aggregation, exploring new helical foldamers for the rational design of protein-protein interaction (PPI) inhibitors, and studying cyclic gamma-AApeptides for antimicrobial development.

<p>The major aim of the studies that this thesis is based on has been to better define the topological determinants of the formation of so-called helical hairpins during membrane protein assembly in the ER membrane.</p><p>The helical hairpin is a basic folding unit in membrane proteins. It is composed of two closely spaced transmembrane helices with a short connecting loop and it is believed to be inserted into the membrane as one compact unit. It is becoming increasingly clear that the helical hairpin is a very common structural element in membrane proteins and a detailed understanding of its properties is of central importance.</p><p>We demonstrate that the efficiency of formation of helical hairpins depends both on the overall length of the hydrophobic segment, on the amino acids flanking the transmembrane segment, and on the identity of the central, potentially turn-forming residues. We also show that interhelical hydrogen bonds between pairs of Asn or Asp residues can induce helical hairpin formation.</p><p>A detailed topology mapping is also reported for the <i>Escherichia coli </i>inner membrane chloride channel YadQ, a protein for which the X-ray structure is known. Our results provide a critical test of the reporter fusion approach and offer new insights into the YadQ folding pathway.</p><p>In summary, the results present in this thesis have increased our understanding of the determinants of membrane protein topology and structure. Furthermore, the information obtained can be used to improve current models for predictions of membrane protein topology.</p>

La magnétohydrodynamique (MHD) est la science et le formalisme qui décrivent les mouvements d'un fluide conducteur d'électricité. Il est possible que de tels mouvements donnent lieu à l'effet dynamo qui consiste en la génération d'un champ magnétique stable et de grande échelle. Ce phénomène est vraisemblablement à l'origine des champs magnétiques des planètes, des étoiles et des galaxies. Il est surprenant qu'alors que les mouvements fluides à l'intérieur de ces objets célestes sont turbulents, les champs magnétiques généré soient de grande échelle spatiale et stables sur de longues périodes de temps. De plus, ils peuvent présenter une dynamique temporelle régulière comme c'est le cas pour le champ magnétique solaire dont la polarité s'inverse tous les onze ans. Décrire et prédire les mouvements d'un fluide turbulent reste l'un des problèmes les plus difficiles de la mécanique classique. %La description aussi bien analytique que numérique d'un fluide hautement turbulent est d'une effroyable complexité, si pas tout simplement impraticable. Dans cette situation, Il est donc utile de construire des modèles aussi proches que possible du système de départ mais de moindre complexité de sorte que des études théoriques et numériques deviennent envisageables. Deux approches ont été considérées ici. D'une part, nous avons développé des modèles présentant un très petit nombre de degrés de liberté (de l'ordre de la dizaine). Une étude analytique est alors possible. Ces modèles ont une dépendance en les paramètres physiques - nombres de Reynolds cinétique et magnétique et injection d'hélicité - qualitativement similaire aux dynamos célestes et expérimentales. D'autre part, les modèles en couches permettent de caractériser les transferts d'énergie entre les structures de différentes tailles présentes au sein du champ de vitesse. Nous avons développé un nouveau formalisme qui permet d'étudier aussi les échanges avec le champ magnétique. De plus, nous proposons une étude de la MHD dans le cadre de la décomposition hélicoïdale des champs solénoïdaux - une idée similaire à la décomposition de la lumière en composantes polarisées et que nous sommes les premiers à appliquer à la MHD. Nous avons montré comment exploiter cette approche pour déduire systématiquement des modèles simplifiés de la MHD. En particulier, nos méthodes multiplient le nombre de situations descriptibles par les modèles en couche comme par exemple le problème anisotrope de la turbulence en rotation. Elles permettent aussi de construire des modèles à basse dimension en calquant les résultats de simulations numériques directes. Ces modèles peuvent alors être étudiés à moindre coûts. _______________ Magnetohydrodynamics (MHD) is both the science and the formalism that describe the motion of an electro-conducting fluid. Such motion may yield the dynamo effect consisting in the spontaneous generation of a large scale stationary magnetic field. This phenomenon is most likely the reason behind the existence of planetary, stellar and galactic magnetic fields. It is quite surprising that also the fluid motion within these objects is turbulent, the generated magnetic fields present large spatial structures evolving over long time scales. Moreover these fields can present a very regular non trivial dynamics like in the case of the Sun, the magnetic field of which switches polarity every eleven years. To describe and predict the motion of a turbulent flow remains one of the most challenging problem of classical mechanics. It is therefore useful to build models as close to the initial system as possible but of a lesser complexity so that their theoretical and numerical analysis become tractable. Two approaches have been considered here. Low dimensional models have been developed that present about ten degrees of freedom. An analytical study of the resulting dynamical system is then possible. Interestingly, the dependance of these models on the physical parameters - kinetic and magnetic Reynolds number as well as injection of kinetic helicity - qualitatively matches that of the cosmic and experimental dynamos. On the other hand, shell models allow to characterise the energy transfers between structures of different sizes within the velocity field. A new formalism is presented which makes possible to also study the exchanges with the magnetic field. Furthermore, a description of MHD in the helical decomposition is proposed. I show how to use this decomposition to build new shell and low dimensional models. The methods developed here allow to broaden the scope of possible applications of the models. In particular, shell models are generalised in such a way that they can now describe anisotropic situations like that of rotating turbulence.

The major aim of the studies that this thesis is based on has been to better define the topological determinants of the formation of so-called helical hairpins during membrane protein assembly in the ER membrane. The helical hairpin is a basic folding unit in membrane proteins. It is composed of two closely spaced transmembrane helices with a short connecting loop and it is believed to be inserted into the membrane as one compact unit. It is becoming increasingly clear that the helical hairpin is a very common structural element in membrane proteins and a detailed understanding of its properties is of central importance. We demonstrate that the efficiency of formation of helical hairpins depends both on the overall length of the hydrophobic segment, on the amino acids flanking the transmembrane segment, and on the identity of the central, potentially turn-forming residues. We also show that interhelical hydrogen bonds between pairs of Asn or Asp residues can induce helical hairpin formation. A detailed topology mapping is also reported for the Escherichia coli inner membrane chloride channel YadQ, a protein for which the X-ray structure is known. Our results provide a critical test of the reporter fusion approach and offer new insights into the YadQ folding pathway. In summary, the results present in this thesis have increased our understanding of the determinants of membrane protein topology and structure. Furthermore, the information obtained can be used to improve current models for predictions of membrane protein topology.

The following study investigates the intramolecular and intermolecular interactions responsible for invoking stereoselectivity and stereospecificity in the synthesis of a chiral original species and amino acid receptor. The former commences with a brief overview of the nature, scope and applications of helical chirality, and culminates in the formation of a permanent helix via the synthesis of a novel chiral lactone. The latter is discussed as an extension of a naturally occurring cofactor whose identity is modulated to furnish a tailored receptor selective to the binding of amino-acid enantiomers. The study and analysis is executed via both synthetic and computational methods.

A synthetic approach to produce lysergic acid by virtue of an asymmetric ring opening (ARO) of symmetrical 3,6-disubstituted-7,10-hydroxymethyl bridgehead substituted oxabicycles is described. The use of a Rhodium(I)/JosiPhos(R,S) catalyst system to effect an ARO using an amine nucleophile furnishes an enantiopure tetrahydronapthalene intermediate with the amine conveniently installed at the 6 position as in lysergic acid, with appropriate stereochemistry; further which, two subsequent annulations are necessary to form the fused 3,5-substituted indole and tetrahydropyridine to complete the synthesis. Progress of this work is described herein along with future directions. The second chapter in this thesis describes the modular and stereoselective synthesis of tetrasubstituted helical alkenes via a palladium-catalyzed domino reaction under Catellani conditions. These helical alkenes possess potentially interesting photochemical properties as molecular motors / switches, and can be applicable in the materials sciences as molecular machines.

The following study investigates the intramolecular and intermolecular interactions responsible for invoking stereoselectivity and stereospecificity in the synthesis of a chiral original species and amino acid receptor. The former commences with a brief overview of the nature, scope and applications of helical chirality, and culminates in the formation of a permanent helix via the synthesis of a novel chiral lactone. The latter is discussed as an extension of a naturally occurring cofactor whose identity is modulated to furnish a tailored receptor selective to the binding of amino-acid enantiomers. The study and analysis is executed via both synthetic and computational methods.

A synthetic approach to produce lysergic acid by virtue of an asymmetric ring opening (ARO) of symmetrical 3,6-disubstituted-7,10-hydroxymethyl bridgehead substituted oxabicycles is described. The use of a Rhodium(I)/JosiPhos(R,S) catalyst system to effect an ARO using an amine nucleophile furnishes an enantiopure tetrahydronapthalene intermediate with the amine conveniently installed at the 6 position as in lysergic acid, with appropriate stereochemistry; further which, two subsequent annulations are necessary to form the fused 3,5-substituted indole and tetrahydropyridine to complete the synthesis. Progress of this work is described herein along with future directions. The second chapter in this thesis describes the modular and stereoselective synthesis of tetrasubstituted helical alkenes via a palladium-catalyzed domino reaction under Catellani conditions. These helical alkenes possess potentially interesting photochemical properties as molecular motors / switches, and can be applicable in the materials sciences as molecular machines.

Reinforced concrete poles are commonly used as street lighting and electrical transmission poles. Typical concrete lighting poles experience very little load due to torsion. The governing design loads are typically bending moments as a result of wind on the arms, fixtures, and the pole itself. The Canadian pole standard, CSA A14-07 relates the helical reinforcing to the torsion capacity of concrete poles. This issue and the spacing of the helical reinforcing elements are investigated. Based on the ultimate transverse loading classification system in the Canadian standard, the code provides a table with empirically derived minimum helical reinforcing amounts that vary depending on: 1) the pole class and 2) distance from the tip of the pole. Research into the minimum helical reinforcing requirements in the Canadian code has determined that the values were chosen empirically based on manufacturer’s testing. The CSA standard recommends two methods for the placement of the helical reinforcing: either all the required helical reinforcing is wound in one direction or an overlapping system is used where half of the required reinforcing is wound in each direction. From a production standpoint, the process of placing and tying this helical steel is time consuming and an improved method of reinforcement is desirable. Whether the double helix method of placement produces stronger poles in torsion than the single helix method is unknown. The objectives of the research are to analyze the Canadian code (CSA A14-07) requirements for minimum helical reinforcement and determine if the Canadian requirements are adequate. The helical reinforcement spacing requirements and the effect of spacing and direction of the helical reinforcing on the torsional capacity of a pole is also analyzed. Double helix and single helix reinforcement methods are compared to determine if there is a difference between the two methods of reinforcement. The Canadian pole standard (CSA A14-07) is analyzed and compared to the American and German standards. It was determined that the complex Canadian code provides more conservative spacing requirements than the American and German codes however the spacing requirements are based on empirical results alone. The rationale behind the Canadian code requirements is unknown. A testing program was developed to analyze the spacing requirements in the CSA A14-07 code. Fourteen specimens were produced with different helical reinforcing amounts: no reinforcement, single and double helical spaced CSA A14-07 designed reinforcement, and single helical specimens with twice the designed spacing values. Two specimens were produced based on the single helical reinforcement spacing. One specimen was produced with helical reinforcement wound in the clockwise direction and another with helical reinforcement in the counter clockwise direction. All specimens were tested under a counter clockwise torsional load. The clockwise specimens demonstrated the response of prestressed concrete poles with effective helical reinforcement whereas the counter clockwise reinforced specimens represented theoretically ineffective reinforcement. Two tip sizes were produced and tested: 165 mm and 210 mm. A sudden, brittle failure was noted for all specimens tested. The helical reinforcement provided no post-cracking ductility. It was determined that the spacing and direction of the helical reinforcement had little effect on the torsional capacity of the pole. Variable and scattered test results were observed. Predictions of the cracking torque based on the ACI 318-05, CSA A23.3-04 and Eurocode 2 all proved to be unconservative. Strut and tie modelling of the prestressing transfer zone suggested that the spacing of the helical steel be 40 mm for the 165 mm specimens and 53 mm for the 210 mm specimens. Based on the results of the strut and tie modelling, it is likely that the variability and scatter in the test results is due to pre-cracking of the specimens. All the 165 mm specimens and the large spaced 210 mm specimens were inadequately reinforced in the transfer zone. The degree of pre-cracking in the specimen likely causes the torsional capacity of the pole to vary. The strut and tie model results suggest that the requirements of the Canadian code can be simplified and rationalized. Similar to the American spacing requirements of 25 mm in the prestressing transfer zone, a spacing of 30 mm to 50 mm is recommended dependent on the pole tip size. Proper concrete mixes, adequate concrete strengths, prestressing levels, and wall thickness should be emphasized in the torsional CSA A14-07 design requirements since all have a large impact on the torsional capacity of prestressed concrete poles. Recommendations and future work are suggested to conclusively determine if direction and spacing have an effect on torsional capacity or to determine the factors causing the scatter in the results. The performance of prestressed concrete poles reinforced using the suggestions presented should also be further investigated. Improving the ability to predict the cracking torque based on the codes or reducing the scatter in the test results should also be studied.