Measuring the level of supply chain robustness during construction mega-projects

Trop souvent, les mégaprojets sont complétés en retard et dépassent les budgets prévus. Néanmoins, il n’existe toujours pas de modèle unique, ni de cadre opératoire, ni de théorie holistique pouvant mesurer les performances et les productivités des divers activités lors de mégaprojets de construction. Une solution proposée par l’auteur de cette thèse est la formulation d'un artefact ou d'un design, appelé modèle de performance et de productivité de la construction (CPPM), qui intègre un cadre opératoire à partir des processus de la chaîne d'approvisionnement. Le modèle de performance et de productivité de la construction fait face à la problématique managériale avec la vision de développer une conception d’attributs et de facteurs clés qui rendrait l'industrie de la construction canadienne plus compétitive. Le cadre du modèle repose sur une approche de chaîne d’approvisionnement, et fournit des facteurs clés de succès en temps réel avec des attributs de performance et des mesures couvrant toutes les phases des mégaprojets. La recherche aux fils des ans a su évoluer grâce à la liberté d’adopter diverses méthodologies et d’étudier plusieurs théories. L’approche de la recherche en design-sciences a donc été choisie parce qu'elle englobe cette liberté académique dans le design managérial, l’approche théorique et l'environnement réel des mégaprojets. Le modèle “CPPM” a révélé que les attributs de performance et les facteurs clés de succès prédominant à l’artefact, étaient ceux reliés aux “EPCM Agility”, suivis des contrôles de coûts et ceux de la fiabilité des achats. L’auteur de cette thèse estime que la recherche entreprit lors de son doctorat a permis à la science de progresser. Cette thèse s'appuie sur ses sept constats liés à la gestion de mégaprojets, renforcée par quatre ans d’observations avec des experts de l’industrie, des entrevues semi-structurées et sondage, de même que la conception d’un modèle “CPPM” qui couvre toutes les phases et activités dans la gestion de mégaprojets. L’auteur a aussi établi un modèle qui est validé par une série de principes, de processus, d’évaluation, de contribution et de justification des connaissances, ainsi que l’originalité et l’inventivité d’un modèle qui est unique et novateur dans la littérature de la gestion de construction. Enfin, l’auteur conclut que l’artefact a atteint un niveau de cohérence que pour le chantier de construction sur lequel il a seulement été testé. Comprenant les limites du modèle, cette recherche offre à d’autres chercheurs l’occasion de renforcer ultérieurement la validité du modèle en le testant sur différents sites de construction.Abstract: Too often mega-projects are completed late and over budget. Nevertheless, there is no holistic model, nor any solid-proof framework, nor theories which measures performance and productivity pertaining to the construction activities. One solution proposed by the researcher, is the formulation of an artifact or design, known as the Construction Performance & Productivity Model (CPPM), which integrates a supply chain framework. The Construction Performance & Productivity Model seeks to attenuate the managerial problematic in the industry with the vision to develop a design that would make the Canadian construction industry more competitive. The framework of the model has a supply chain approach, provides real-time measurement with performance attributes and metrics that are pertinent to the construction industry. It is also friendly to users and covers all phases of construction mega-projects. The research over the years evolved from the freedom of adopting various methodologies and theories. The paradigm of Design-Science Research (DSR) was selected because it espouses this academic freedom in design, science and real-life environment. Through a Participant Observation (engineering phases) and Action Research (construction activities), using the SCOR Model as its base, enriched and minimised through a series of semi-structures interviews and one survey, the research found the most important performance attributes and metrics that performed best in the model (CPPM) were the ones belonging to the categories of EPCM Agility, followed by Project Controls and Procurement Reliability. The researcher believes this doctoral thesis has permitted the science to progress because its model (CPPM) relates its seven (7) constructs to megaprojects, reinforced by four (4) years of observations, is validated through a series of principles, processes, evaluation, contribution and justification knowledge. Moreover, the model’s originality and inventiveness are different from the ones found in construction literature. Finally, the researcher concludes the CPPM has achieved a level of consistency for the construction site it was only tested to it. Understanding the model’s limitations, this research offer opportunities to other scientists to further the model validity by testing it in different construction sites

Des Amazones parmi les pères de l'église : témoignage de la condition féminine durant la période de l'église primitive

Syncretism in the religion of Christianity has been an important, if not the most crucial aspect of its survival. This is even more true about the Early Christianity period, its first six centuries. In this study, the story of the Amazons is scrutinized in order to see what the Fathers of the Church have said about these 'barbarian' women. Since the main concern for the time was to convert pagan citizen to Christianity and as the social context of this conversion was set in a most patriarcal society, syncretism created the Amazons as an example of the non-christian women, therefore an example of what to not do. As this can be said for the whole period, nuances are shown in the tone used which reflects the century, the region, the background and the purposes influencing each individual. Overall, this magnificent story of the Amazons, part of Greek mythology, carries within its lines the stigma imbeded by the pagans and propagated by Christians to uphold in their own beliefs

DHA Improves Cognition and Prevents Dysfunction of Entorhinal Cortex Neurons in 3xTg-AD Mice

Defects in neuronal activity of the entorhinal cortex (EC) are suspected to underlie the symptoms of Alzheimer's disease (AD). Whereas neuroprotective effects of docosahexaenoic acid (DHA) have been described, the effects of DHA on the physiology of EC neurons remain unexplored in animal models of AD. Here, we show that DHA consumption improved object recognition (↑12%), preventing deficits observed in old 3xTg-AD mice (↓12%). Moreover, 3xTg-AD mice displayed seizure-like akinetic episodes, not detected in NonTg littermates and partly prevented by DHA (↓50%). Patch-clamp recording revealed that 3xTg-AD EC neurons displayed (i) loss of cell capacitance (CC), suggesting reduced membrane surface area; (ii) increase of firing rate versus injected current (F-I) curve associated with modified action potentials, and (iii) overactivation of glutamatergic synapses, without changes in synaptophysin levels. DHA consumption increased CC (↑12%) and decreased F-I slopes (↓21%), thereby preventing the opposite alterations observed in 3xTg-AD mice. Our results indicate that cognitive performance and basic physiology of EC neurons depend on DHA intake in a mouse model of AD

The Transcription Factor E4F1 Coordinates CHK1-Dependent Checkpoint and Mitochondrial Functions

Recent data support the notion that a group of key transcriptional regulators involved in tumorigenesis, including MYC, p53, E2F1, and BMI1, share an intriguing capacity to simultaneously regulate metabolism and cell cycle. Here, we show that another factor, the multifunctional protein E4F1, directly controls genes involved in mitochondria functions and cell-cycle checkpoints, including Chek1, a major component of the DNA damage response. Coordination of these cellular functions by E4F1 appears essential for the survival of p53-deficient transformed cells. Acute inactivation of E4F1 in these cells results in CHK1-dependent checkpoint deficiency and multiple mitochondrial dysfunctions that lead to increased ROS production, energy stress, and inhibition of de novo pyrimidine synthesis. This deadly cocktail leads to the accumulation of uncompensated oxidative damage to proteins and extensive DNA damage, ending in cell death. This supports the rationale of therapeutic strategies simultaneously targeting mitochondria and CHK1 for selective killing of p53-deficient cancer cells

Autonomous quantum error correction of Gottesman-Kitaev-Preskill states

The Gottesman-Kitaev-Preskill (GKP) code encodes a logical qubit into a bosonic system with resilience against single-photon loss, the predominant error in most bosonic systems. Here we present experimental results demonstrating quantum error correction of GKP states based on reservoir engineering of a superconducting device. Error correction is made autonomous through an unconditional reset of an auxiliary transmon qubit. The lifetime of the logical qubit is shown to be increased from quantum error correction, therefore reaching the point at which more errors are corrected than generated.Comment: 6 pages, 3 figures + 26 pages, 12 figure

Assessment of pre-clinical liver models based on their ability to predict the liver-tropism of AAV vectors

The liver is a prime target for in vivo gene therapies using recombinant adeno-associated viral vectors (rAAV). Multiple clinical trials have been undertaken for this target in the past 15 years, however we are still to see market approval of the first liver-targeted AAV-based gene therapy. Inefficient expression of the therapeutic transgene, vector-induced liver toxicity and capsid, and/or transgene-mediated immune responses reported at high vector doses are the main challenges to date. One of the contributing factors to the insufficient clinical outcomes, despite highly encouraging preclinical data, is the lack of robust, biologically- and clinically-predictive preclinical models. To this end, this study reports findings of a functional evaluation of six AAV vectors in twelve preclinical models of the human liver, with the aim to uncover which combination of models is the most relevant for the identification of AAV capsid variant for safe and efficient transgene delivery to primary human hepatocytes. The results, generated by studies in models ranging from immortalized cells, iPSC-derived and primary hepatocytes, and primary human hepatic organoids to in vivo models, increased our understanding of the strengths and weaknesses of each system. This should allow the development of novel gene therapies targeting the human liver

mRNA therapy corrects defective glutathione metabolism and restores ureagenesis in preclinical argininosuccinic aciduria

The urea cycle enzyme argininosuccinate lyase (ASL) enables the clearance of neurotoxic ammonia and the biosynthesis of arginine. Patients with ASL deficiency present with argininosuccinic aciduria, an inherited metabolic disease with hyperammonemia and a systemic phenotype coinciding with neurocognitive impairment and chronic liver disease. Here, we describe the dysregulation of glutathione biosynthesis and upstream cysteine utilization in ASL-deficient patients and mice using targeted metabolomics and in vivo positron emission tomography (PET) imaging using ( S)-4-(3-18F-fluoropropyl)-l-glutamate ([18F]FSPG). Up-regulation of cysteine metabolism contrasted with glutathione depletion and down-regulated antioxidant pathways. To assess hepatic glutathione dysregulation and liver disease, we present [18F]FSPG PET as a noninvasive diagnostic tool to monitor therapeutic response in argininosuccinic aciduria. Human hASL mRNA encapsulated in lipid nanoparticles improved glutathione metabolism and chronic liver disease. In addition, hASL mRNA therapy corrected and rescued the neonatal and adult Asl-deficient mouse phenotypes, respectively, enhancing ureagenesis. These findings provide mechanistic insights in liver glutathione metabolism and support clinical translation of mRNA therapy for argininosuccinic aciduria. </p