The proposition presented in this thesis is that the use of the "Agreed Charges" by the Canadian railroads was designed merely as an instrument to improve their place in the growing intermodal competition in Canadian transport. However, the thesis has revealed potential effects for the Canadian economy extending beyond this purpose. These effects grow out of the influence that Agreed Charges have had on the marketing "reach" of Canadian manufacturers, and the consequential location of industry. The competitive purpose of Agreed Charges is reviewed by a study of their origin and effects in transportation in England preceding any experience with them in Canada. This is followed by reference to Canadian legislation of 1938 which presented the detailed legislation authority for Agreed Charges as they developed in Canada. The basic competitive purpose of the new rate device is evaluated by a study of its effects on the railroads and their competitors. The effects of Agreed Charges on the Canadian economy going beyond this competitive purpose is then studied through describing and appraising the influence which they had on the inter-regional marketing of a number of. products. Through this study the influence shows itself in permitting enlarged production in certain regions in Canada by extending the marketing areas beyond those that could be reached without Agreed Charges; and it shows itself in the preferences it gave to Canadian manufactured products over competitive products from abroad. / Business, Sauder School of / Graduate

Anti-insider trading provisions were initially enacted to inter alia; enhance confidence in South African financial markets by contributing to the maintenance of a stable financial market environment by promoting the international competitiveness of investors in securities services in the country. In attempts to determine whether the Insider trading regulations are indeed effective at deterring insider trading contraventions as well as enforcing contraventions thereof, the research will subsequently examine the relevant legislation which pertains to insider trading in South Africa as well as analyse any definitional ambiguities and difficulties caused therein. Wherefore other than where the definitions in the legislation is lacking, the research will further discuss what additional problems are drawn from the current legislative insider trading framework. An analysis will be done regarding the difficulties experienced by the Financial Sector Conduct Authority (hereafter the FSCA or the Regulator) as the entity responsible for the supervision of compliance with market abuse provisions in discharging of its duties as a result of the current legislation and/or the lack of clarity therefore. A comparative study will consequently be conducted in the research to establish how Australia has arguably become acknowledged to have the most progressive and developed market abuse legislation in the world compared to that of South Africa. Ultimately, recommendations will be presented using the above comparisons on what mechanisms can be adopted to improve on South Africa’s regulation of insider trading. / Mini Dissertation (LLM (Corporate Law))--University of Pretoria, 2020. / Mercantile Law / LLM / Unrestricted

The Law and Regulation of ICO (Initial Coin Offering) Abstract This diploma thesis deals with legal analysis of ICO (Initial Coin Offering) and legal analysis of tokens that are issued within an ICO. The thesis aims to find out whether and to what extent an ICO is subjected to initial public offering law and whether the tokens can be characterized as things, securities, dematerialized securities, and electronic money. In the first part of the thesis, I define the basic concepts and terms. Definitions and terms are supplemented by the technical and economic background of each respective institute. The first part also briefly summarizes the historical development of ICO, which shaped it into its present form. The second part of the thesis deals with the legal categorization of tokens. Firstly conceptual features of the thing in the legal sense, dematerialized security, security, and electronic money are established. Subsequently, it is examined whether the tokens can fall within these conceptual features or not. In the chapter regarding securities, it is pointed out that different understanding of securities in public and private law may have some negative consequences. The analysis of the contractual relationship between the issuer and the investor is also addressed in the second part. In the third part, ICO...

Current models of exercise regulation almost solely rely on the Gestalt phenomenon of perceived exertion. This limits a more comprehensive understanding of how causeeffect relationships come to be and how perception-action coupling determines pacing behaviour and performance fatigability. A three-dimensional framework of centrally regulated and goal-directed exercise behaviour is proposed, which differentiates between sensory-discriminatory, affectivemotivational, and cognitive-evaluative processes hypothesised to underpin perceived fatigability. In short: (A) perceived physical strain and perceived mental strain are primary regulators of pacing behaviour necessary to align planned behaviour with current physiological state, (B) core affect plays a primary and mediatory role in performance regulation, and (C) the mindset- shift associated with an action crisis plays a primary role in volitional self-regulatory control and decision-making. In study one, 23 cyclists of distinct performance levels engaged in 70-km individual and head-to-head competition time trials against a performance matched opponent. Sensory constructs were primarily associated with regulation of pacing behaviour. Affective and cognitive constructs acted as context-dependent modifiers and were primarily associated with regulation of performance. A five-step structural equation modelling procedure was applied to assess the extent to which the observed data fit the hypothesised cause–effect relationships under the constraint of psychological duress: valence deterioration was found to mediate the relationship between falling-behind and action crisis; which in turn predicted increased non-adaptive endocrinological distress response; which in turn predicted performance decrement. In study two, 22 highly-trained runners completed two self-paced 20-km treadmill time trials in a tapered condition and with locomotor muscle fatigue and exercise-induced muscle damage. The latter was associated with medium increases in markers of physiological distress and large alterations in perceived physical strain, affective valence, and cognitive mindset. This indicates heuristic and rational antecedents in the goal-disengagement process. Structural equation modelling confirmed the hypothesised dual-pathway model under the constraint of physical duress: haematological indicators of EIMD predicted (1) amplified physiological strain and non-adaptive endocrinological distress response and (2) increase in perceived physical strain, which mediated and predicted decrease in valence; which in turn predicted an increase in action crisis; and both physiological and perceptual effects predicted performance fatigability. The proposed framework has the potential to enrich theory development in centrally regulated and goal-directed exercise behaviour by providing novel insights into and more complete account of the dynamic and complex processes in strain-perceptionthinking-action coupling during prolonged endurance exercise.

Despite the steady growth of electronic commerce (e-commerce), Lesotho and SADC users are uncertain of how to securely sign e-communications practicably. This results in users' lack of confidence in the use of e-commerce. SADC and Lesotho regulatory bodies have developed legal instruments including model laws and bills in an attempt to regulate electronic signatures (e-signatures) in e-commerce to address this problem amongst others. However, it is unclear whether the approach adopted will ensure that the regulatory instruments effectively regulate e-signatures and consequently promote the growth of e-commerce and enhance the socio-economic development of the state. This study examines what the information and communications technology regulatory principles of functional equivalence and technology neutrality entail, their interpretation by the United Nations Commission on International Trade Law (UNCITRAL), and their appropriateness for effective regulation of e-signatures through conceptual analysis. In particular it examines the UNCITRAL Model Laws on e-commerce, UNCITRAL Model on e-signature and the United Nations Convention on the Use of Electronic Communications in International Contracts. The study describes the technical operation of different offline and online signatures in order to appreciate how e-signatures should be regulated. Through textual analysis, it examines whether regulatory instruments of Lesotho and SADC correctly apply the theories in a way that will render use of e-signatures practicable and their regulation effective. It also examines initiatives on regulation of e-signatures in South Africa, the United States of America and the European Union. The study reveals that the purpose of the signature formality is to promote certainty, prevent fraud and provide evidence of a contract despite the form of signature. Although not perfect, functional equivalence and technology neutrality principles render regulation of electronic signatures effective since rules that align with them promote equivalence of legal treatment between offline and online signatures. Consequently, the UNCITRAL's Convention reflects that ordinary e-signatures can meet purposes of the signature formality where appropriate if they observe its functional equivalence criteria. However, the reliability of such electronic signatures is a question of evidence as is the case in offline contracts. Thus, soft laws on electronic evidence must complement the e-signature rules to ensure equivalent legal treatment of signatures. The study reveals that the Lesotho instruments do not fully align with the regulatory principles whereas the SADC instrument closely aligns with them. To different extents, these instruments do not adequately address the problems of users and may inhibit the growth of e-commerce. It further found that the instruments erroneously exclude certain matters such as wills from e-signature application while they correctly exclude others such as negotiable instruments from e-signature application. Lastly it found that the UNCITRAL convention and the US instruments provide better models for effective regulation of e-signatures. By implementing amendments suggested by this study, Lesotho and SADC will address the challenges faced by e-commerce users and make the use of e-signatures feasible for all. Consequently, the instruments will effectively increase the growth of e-commerce and in turn enhance the development of socio economic growth of the SADC region.

Positive affect, which has been broken down into four lower-level facets (i.e., joviality, attentiveness, self-assurance, serenity), has demonstrated numerous ties to physical and mental health. The experience of positive affect can be regulated by emotion regulation strategies. However, few studies have assessed their relationship, and no studies have examined the relationship using the lower level facets of positive affect. The link between positive affect and emotion regulation may be of particular importance for individuals at increased risk for bipolar disorder, as both are disrupted in individuals with the condition. The aim of the present study was to examine the relationship between positive affect and emotion regulation while also exploring whether risk for bipolar disorder moderated their relationship. Undergraduates (N = 155) completed measures of emotion regulation, affect, and bipolar disorder risk at baseline. Using ecological momentary assessment (EMA), participants completed surveys 3 times a day for 7 days. Hierarchical linear models were estimated and revealed significant effects between certain baseline emotion regulation tendencies (experiential avoidance/ psychological inflexibility, rumination, behavioral social avoidance) and daily positive affect facets as well as between daily emotion regulation use (i.e., reappraisal, acceptance, reflection, savoring, mindfulness social support, suppression, rumination, procrastination) and daily positive affect facets. Bipolar disorder risk was not found to moderate the relationship. Findings support the use of strategies emphasized in evidence-based treatments and highlight the importance of daily practice of emotion regulation skills.

The day-to-day physiologies are largely influenced by circadian rhythms. Disruptions of such rhythms are associated with many diseases. Adjusting them to a healthy one can be promising to treat different circadian rhythms disruption associated diseases such as sleep disorders, cardiovascular disorders, metabolic disorders. The regulations underlying the circadian rhythms are much complicated and systematic which may involve thousands of genes. In mammals, these robust circadian rhythms are primarily intended by the concerted molecular interplays, knowingly, transcriptional-translational feedback loops (TTFLs). The collaborative interactions among a large number of genes intend to sustain the TTFLs. It facilitates to generate the primary transcriptional oscillations among the clock genes and genome-wide rhythmic oscillations. The collaborative transcriptional events act as dominant driving forces underpinning such rhythmic expressions. The mode of the transcriptional regulations depends on the concentration of the transcriptional factors (TFs) at the promoter region at a particular time point. The inclusive mechanisms of their regulations and the associated circadian rhythmic outputs across the physiology are not well defined yet. However, temporal recruitment of core-clock proteins, different transcriptional and translational regulators and chromatin modifications are imperative towards a comprehensive understanding of the spatio-temporal regulation of such complex rhythms. Despite many experimental signs of progress about the circadian transcriptional controls, there is still an interesting question remains unexplored that how do these few components belonging to the same molecular architecture are capable to govern such divergent gene expressions? Nevertheless, how they are being regulated and the landscape of their combinatorial regulatory controls have not gained any inclusive attention yet. Thus, a systematic understanding considering all-encompassing circadian TFs and their relational interplay could help us to decode the intricated transcriptional regulatory logics composed by different TFs. Such comprehensive understanding may lead to unleashing their potential to therapeutically modulate the circadian rhythms. Experiments alone are indeed quite challenging to achieve this. Decoding the inclusive transcriptional insights along with multifaceted molecular regulations remained out of reach with prevailing approaches. They are limited by the complexities of more integrative algorithms that accommodate different layers of molecular information quantitatively into a single framework. Studies indicated the knockout of the circadian TFs results in changing the rhythms. And, rescuing them helps to regain the circadian functionality substantially. However, knocking out all possible combinations of circadian TF-genes experimentally is merely very tedious, time-consuming and expensive. And, some essential genes cannot be knocked out. The magnitude of disruption of the circadian rhythmic fluctuations may also vary in disease conditions and even from individual to individual. These are serious concerns which were weakly understood. Due to the lack of advanced quantitative approach, these have remained a great challenge with traditional practices for reversing the disrupted circadian rhythms. Another level of challenge is not only aligning the rhythms but also, having a strong understanding of the directionality of the alignment varying in different clinical contexts is the most crucial. Consequently, a thorough quantitative understanding at the molecular level of the clock control mechanisms is essential. To address these ambiguities, a quantitative understanding of the circadian gene regulation and the molecular interplay among the key regulators are quite important. An alternative yet the operative approach is the reconstruction of transcriptional network with those genes having circadian fluctuations by computational simulations. It may capture a systematic snapshot of such gene regulation network at a dynamic scale. Inferring them is again a complicated task as the large numbers of variables are unknown in the systems. There is also a lack of tools to capture and integrate the dynamic view which is biologically relevant. Virtual knockout experiments leverage in inferring such dynamic transcriptional regulatory networks iteratively and effectively. The molecular machinery underpinning the circadian rhythms possess high-temporal resolutions. Thus, it is also quite challenging to construct the network of those genes under the influence of TTFLs at dynamic scale using existing methods. Most of the prevailing approaches are quite limited by the quantitative understanding of the transcriptional landscape thoroughly. Recently, one of our computational approaches, LogicTRN was proposed for modelling the transcriptional regulatory networks quantitatively. Deploying the high-resolution temporal gene expression data and the TF-DNA binding data, it calculates the TF-DNA binding occupancy, which is a quantitative estimation. It also predicts the all possible combinatorial TF-logics influencing those target genes' regulations. Here, we introduced an extended computational approach based on LogicTRN to decode the quantitative transcriptional regulatory landscapes of circadian genes. We introduced the reconstruction of quantitative transcriptional regulatory networks (qTRNs) for circadian gene regulations using LogicTRN framework. The qTRNs facilitated to discover a wide range of genes exhibiting circadian fluctuations. Their dynamic behaviours and the cis-regulatory logics in the networks were also estimated precisely. Based on quantitative knowledge from qTRNs, we have further developed a method for virtually knocking out the core clock component TFs to estimate the influence to perturb the circadian rhythmic fluctuations at a dynamic scale. Consecutively, the method of single/multiple genes virtual knockout was developed and used to screen the best TF/TFs combination that effectively modulates the circadian rhythmic output at a dynamic scale. They were also ordered by their influence to perturb the circadian fluctuations in the qTRNs. In future, it may indicate a way to target the molecular regulators to therapeutically modulate the circadian period lengths in a specific direction based on an individual's clinical conditions. Our results indicate the reconstruction of highly accurate quantitative regulatory networks for the transcriptional controls of the circadian gene regulation at a dynamic scale. We have also identified the best plausible transcription factors or their combinations those can effectively modulate the circadian rhythms. Of them, the CLOCK and CRY1 double knockout preserve the highest capacity to modulate the circadian rhythm dynamics. Besides, all possible TFs/TF-combinations were ordered in terms of their capacity to influence the qTRNs at dynamic scales. Finally, our quantitative framework offers a quick, robust, and physiologically relevant way to screen and identify the most effective TFs/TF-combinations to modulate circadian rhythms. This foundation may potentially enable us to engineer the molecular regulators underpinning the circadian rhythms. This potentially indicates a clue towards adjusting the circadian rhythmic phases in desired directions depending on clinical requirements

UHRF1 is an essential epigenetic regulator implicated in the maintenance of DNA methylation. While its functional state has been suggested to be allosterically regulated by phosphatidylinositol 5-phosphate and dependent on purification conditions and tags coupled to the protein, the expression system might have a broader impact on UHRF1s interaction properties. We hypothesized that the translation kinetics defined by the expression host has an impact on the folding process of the protein, which ultimately affects its structure and function. To test this idea, the cDNA of UHRF1 was recoded in order to generate optimized and harmonized sequences that were expected to alter the overall translation speed. Both proteins were expressed in Escherichia coli BL21-DE3 and their interaction profiles with H3K9me3 and unmodified H3 peptides were determined by microscale thermophoresis assays. The dissociation constants were compared by ttests in order to evaluate a possible change in the interaction properties of the optimized and harmonized proteins, compared to non-optimized UHRF1 expressed in E. coli BL21-DE3. While no difference was found for the interaction of optimized UHRF1 with the H3K9me3 peptide, a significant difference was found for its interaction with the unmodified H3 peptide. Moreover, both the interactions of harmonized UHRF1 with H3K9me3 and unmodified H3 peptides were determined to change. For this reason, we concluded that translation kinetics dependent on the expression system impacts the functional state of UHRF1. To further study this phenomenon, we expressed the consensus sequence of UHRF1 in Escherichia coli BL21-Codon Plus-(DE3)-RIL, a bacterial strain that is enriched with arginine, isoleucine, and leucine tRNA isoacceptors. Differences in its interaction profile with histone peptides were found when compared with UHRF1 expressed in Escherichia coli BL21-DE3. Since the major difference between these strains is the abundance of tRNAs, we obtained further findings that support our initial hypothesis. Additionally, the interaction profiles from the consensus UHRF1 protein were determined in the presence of PI5P to get an insight into how this phosphoinositide might impact the final structure and function of UHRF1. MST measurements and limited proteolysis assays led us to the idea of a partially open conformation for the UHRF1 expressed in E. coli BL21-DE3 and E.coli Codon Plus-(DE3)-RIL.

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