La valorisation de résidus agricoles, industriels ou urbains se révèle, à mesure des recherches et des avancées, un recours pertinent aux défis s’imposant à l’industrie de la terre cuite et au domaine de l’habitat. L’incorporation de résidus agricoles à travers des produits conventionnels a permis au long de cette étude une économie de ressource argileuse et d’énergie, tout en améliorant les performances mécaniques et thermiques à la base des matériaux de construction. Des matières végétales ajoutées au mélange argileux de fabrication entrainent une formation de porosité, durant la cuisson des produits, selon la libération d’espaces occupés par les particules, à des températures allant de 200 à 400°C. Les pores en formation adoptent alors les formes et les tailles de particules constitutives, en procurant une maitrise de la microstructure et des propriétés usuelles de la terre cuite. Les résidus agricoles à fines particules se décomposent au sein de la matrice argileuse et procurent, en réduisant la taille moyenne des pores, une amélioration des performances mécaniques de près de 40%. Les matières végétales à particules fibreuses suscitent en revanche une augmentation de l’anisotropie originelle de la microstructure et une amélioration notable de 40% des performances thermiques. La combustion de la matière organique assure, en prime, un apport énergétique au procédé de cuisson s’élevant à 35% des besoins en combustible et compensant un coût d’achat éventuel. L’incorporation de matières végétales au sein des produits de terre cuite apparait comme un succès sur le plan économique, environnemental et technique en raison d’une valorisation matière, entrainant une amélioration des performances usuelles, et d’une valorisation énergétique, accordant une réduction des consommations en gaz et des émissions en dioxyde de carbone. / Waste and biomass valorization appears, on a way of research and advances, as a relevant answer in the challenge offered to the clay bricks industry and housing field. Incorporations of agricultural wastes into clayey ceramic bodies accorded, along those investigations, raw material and energy savings, since improving the mechanical and thermal properties on the basis of every building material. Biomass incorporations amongst argillaceous mixtures induce a porosity formation through the firing process under a release, on a range of temperatures going from 200 to 400°C, of the material spaces previously filled by the organic particles. The porous cavities assume the sizes as well as shapes of the biomass particles and provide a microstructure control affording a functional properties command. The agricultural wastes including thin particles fade out into the clayey bodies and provide, through a median pore size reduction, an improvement of the mechanical strength up to 40%. Crops residues showing fibrous particles induce on the other hand an increase of microstructure and porous network anisotropy, leading to a tremendous improvement of nearly 40% in the insulation behavior. The biomass combustion provides a calorific contribution as well, to the industrial process of firing, surrounding 35% of the usual fuel requirements and supplies an eventual cost of agricultural wastes. Biomass incorporation into clayey ceramic appears as a success on economical, environmental and technical terms, according to the material purpose offering an improvement of the functional performances, and energy purpose assuming a diminution of gas consumptions or a reduction of carbon dioxide release.

Background: The rapidly changing world of digital technologies forces many companies to undertake a digital shift by transforming existing business models into digital business models to achieve sustainable value creation and value capture. Especially, for established companies, that have been successful leaders before the dot-com bubble (1995-2000) and whose business models have been threatened by the emergence of digital technologies, there is a need for a digital shift. We refer to this digitization of business models as digital business model innovation. However, often adoption and implementation of digital technologies require tremendous changes and thus, can be challenging for established companies. Therefore, agile methods and business experimentation have become important strategic elements and are used to generate and test novel business models in a fast manner. We introduce lean startup as an agile method for digital business model innovation, which has proven to be successful in digital entrepreneurship. Thus, it requires further empirical investigation on how to use lean startup in established companies for successful digital business model innovation. Purpose: The purpose of our study is to identify enablers and barriers of lean startup as a tool for digital BMI in established companies. Thus, we propose a framework showing how established companies can be successful in digital business model innovation by using lean startup. Method: We conducted exploratory, qualitative research based on grounded theory following an abductive approach. Using a non-probability, purposive sampling strategy, we gathered our empirical data through ten semi-structured interviews with experts in lean startup and digital business model innovation, working in or with established companies, shifting their business model towards a digital business model. By using grounded analysis, we gained an in-depth understanding of how lean startup is used in practice as well as occurring barriers and enablers for established companies. Conclusion: We emphasize that successful use of lean startup for digital business model innovation is based on an effective (1) lean startup management, appropriate (2) organizational structures, fitting (3) culture, and dedicated (4) corporate governance, which all require and are based on solid (5) methodical competence of the entire organization. Furthermore, (6) external influences such as market conditions, role of competition, or governance rules indirectly affect using lean startup as a tool for digital business model innovation.

In Sweden, it is expected that more than 90% of the population will live in cities by 2040. Therefore, cities have an important role in sustainable development to ensure high quality of life in the face of climate change and social challenges. This thesis uses the framework of Urban Living Labs as a form of experimentation to analyse how evaluation and learning in municipalities take place. Districts identified as sites of experimentation in the six mid-sized municipalities Umeå, Gävle, Jönköping, Borås, Örebro, and Lund are studied using a multiple case study approach. Secondary data is discussed together with findings from interviews. The results show that the aims and challenges of experimentation are similar in all cases. Municipalities aim at increasing their attractivity with these extraordinary districts, but they also contribute to sustainable development through innovation in different sectors (e.g., energy, construction, social life). The importance of structured evaluation for learning is recognized, but only few have (as of now) developed a framework for this. Double-loop learning (or reflectivity) is hinted at in the interviews, but for most projects, it is too early to identify whether it will take place. Experiments are contributing to sustainable development on a larger scale mostly through interactions in networks. Personal Networks, as well as international networks (e.g., initiated by the EU), have a special role as these provide incentives for experimentation, quick informal exchange, as well as spread findings and knowledge to municipalities outside of Sweden.

Increasingly complex dynamics in the software operations pose formidable software evolution challenges to the software industry. Examples of these dynamics include the globalization of software markets, the massive increase of interconnected devices worldwide with the internet of things, and the digital transformation to large-scale cyber-physical systems. To tackle these challenges, researchers and practitioners have developed impressive bodies of knowledge, including adaptive and autonomic systems, run-time models, continuous software engineering, and the practice of combining software development and operations (i.e., DevOps). Despite the tremendous strides the software engineering community has made toward managing highly dynamic systems, software-intensive industries face major challenges to match the ever-increasing pace. To cope with this rapid rate at which operational contexts for software systems change, organizations are required to automate and expedite software evolution on both the development and operations sides. The aim of our research is to develop continuous and autonomic methods, infrastructures, and tools to realize software evolution holistically. In this dissertation, we shift the prevalent autonomic computing paradigm and provide new perspectives and foci on integrating autonomic computing techniques into continuous software engineering practices, such as DevOps. Our methods and approaches are based on online experimentation and evolutionary optimization. Experimentation allows autonomic managers to make in- formed data-driven and explainable decisions and present evidence to stakeholders. As a result, autonomic managers contribute to the continuous and holistic evolution of design, configuration and deployment artifacts, providing guarantees on the validity, quality and effectiveness of enacted changes. Ultimately, our approach turns autonomic managers into online stakeholders whose contributions are subject to quality control. Our contributions are threefold. We focus on effecting long-lasting software changes through self-management, self-improvement, and self-regulation. First, we propose a framework for continuous software evolution pipelines for bridging offline and online evolution processes. Our framework’s infrastructure captures run-time changes and turns them into configuration and deployment code updates. Our functional validation on cloud infrastructure management demonstrates its feasibility and soundness. It effectively contributes to eliminate technical debt from the Infrastructure-as-Code (IAC) life cycle, allowing development teams to embrace the benefits of IAC without sacrificing existing automation. Second, we provide a comprehensive implementation for the continuous IAC evolution pipeline. Third, we design a feedback loop to conduct experimentation-driven continuous exploration of design, configuration and deployment alternatives. Our experimental validation demonstrates its capacity to enrich the software architecture with additional components, and to optimize the computing cluster’s configuration, both aiming to reduce service latency. Our feedback loop frees DevOps engineers from incremental improvements, and allows them to focus on long-term mission-critical software evolution changes. Fourth, we define a reference architecture to support short-lived and long-lasting evolution actions at run-time. Our architecture incorporates short-term and long-term evolution as alternating autonomic operational modes. This approach keeps internal models relevant over prolonged system operation, thus reducing the need for additional maintenance. We demonstrate the usefulness of our research in case studies that guide the designs of cloud management systems and a Colombian city transportation system with historical data. In summary, this dissertation presents a new approach on how to manage software continuity and continuous software improvement effectively. Our methods, infrastructures, and tools constitute a new platform for short-term and long-term continuous integration and software evolution strategies and processes for large-scale intelligent cyber-physical systems. This research is a significant contribution to the long-standing challenges of easing continuous integration and evolution tasks across the development-time and run-time boundary. Thus, we expand the vision of autonomic computing to support software engineering processes from development to production and back. This dissertation constitutes a new holistic approach to the challenges of continuous integration and evolution that strengthens the causalities in current processes and practices, especially from execution back to planning, design, and development. / Graduate

Synaptic plasticity, in its broadest sense, can be defined as the ability of synapses to be modified structurally and functionally in response to various internal and external factors. Growing evidence has established that at the very core of these modifications are alterations in the cytoskeletal architecture. This discovery has led to the unearthing of a number of signaling pathways that might be involved in cytoskeletal regulation and also in the regulation of other aspects of synapse development and plasticity. In this regard, polarity proteins and secreted morphogens such as the Wnt proteins, typically involved in embryonic development, are emerging as critical determinants of synaptic growth and plasticity. However, their mechanism of action at synapses needs further investigation. Additionally, not much is known about how these morphogens are secreted or transported across synapses. Using the Drosophila larval NMJ as a model system, I have addressed aspects related to the issues mentioned above in the subsequent body of work. In the first half of my thesis, I have uncovered a role for the aPKC/Baz/Par-6 polarity protein complex in the regulation of the postsynaptic actin cytoskeleton in conjunction with the lipid and protein phosphatase PTEN. In the second half of my thesis, I have contributed to the elucidation of mechanisms underlying the secretion of Wg, the Drosophila Wnt homolog. Our findings suggest that Wnts might be secreted via a previously unidentified mechanism involving the release of exosome like vesicles from the presynapse and this process requires Evi/Wntless (Evi), a protein dedicated to Wnt secretion. Alterations in signaling pathways and aberrant cytoskeletal regulation lead to a variety of neurological disorders. The body of work in this thesis will provide a deeper understanding of the mechanisms involved in synaptic plasticity and provide a basis for uncovering similar pathways in the context of vertebrate synapses.

Every fall, Northeastern America monarch butterflies (Danaus plexippus) undergo an extraordinary migration to their overwintering site in Central Mexico. During their long migration, monarch migrants use sun compass to navigate. To maintain a southward flying direction, monarch migrants compensate for the continuously changing position of the sun by providing timing information to the compass using their circadian clock. Animal circadian clocks depend primarily on a negative transcriptional feedback loop to track time. I started my work to re-construct the monarch butterfly circadian clock negative feedback loop in cell culture, focusing on homologs of Drosophila clock genes. It turned out that in addition to a Drosophila-like cryptochrome (cry1) gene, a second mammalian-like cry2 gene exists in monarch butterflies and many other insects, except in Drosophila. The two CRYs showed distinct functions in our initial assays in cultured Drosophila Schneider 2 (S2) cells. CRY2 functions as a potent transcriptional repressor, while CRY1 is light sensitive but shows no obvious transcriptional activity. The existence of two cry genes in insects changed the Drosophila-centric view of insect circadian clock. During the course of my study, our lab obtained a monarch cell line called DpN1 cells. These cells possess a light-driven clock and contributed tremendously to the research on monarch circadian clock. Using this cell line, I provided strong evidence supporting monarch CRY2’s role as a major circadian clock repressor and identified a protein-protein protective interaction cascade underlying the CRY1-mediated resetting of the molecular oscillator in DpN1 cells. I continued my work trying to understand how insect CRY2 inhibits transcription. I provided evidence suggesting the involvement of monarch PER in promoting CRY2 nuclear entry in both S2 cells and DpN1 cells. Finally, I mapped CRY2’s transcriptional inhibitory activity onto its N-terminal domain. Collectively, my research helped to change our view of insect clocks from a Drosophila-centric standpoint to a much more diverse picture. My studies also advanced the understanding of monarch circadian clock mechanism, and provides a foundation for further studies.

The pancreas is located below the liver and adjacent to the small intestine where it connects to the duodenum. It consists of exocrine and endocrine components. The exocrine portion makes enzymes which are deposited in the duodenum to digest fats, proteins, and carbohydrates. Exocrine tissue also makes bicarbonates that neutralize stomach acids. The endocrine portion produces hormones such as insulin and glucagon which are released into the blood stream. These hormones regulate glucose transport into the body's cells and are crucial for energy production. The pancreas is associated with diseases such as cancer, diabetes, Annular pancreas and Nesidioblastosis. Annular pancreas and Nesidioblastosis are congenital malformations associated with excess endocrine tissue of the pancreas and its structures. Understanding the development of the pancreas might lead to insight of these diseases. The pancreas arises from the endoderm. In zebrafish, Nodal signaling activates mix-type and gata genes that then function together to regulate sox32 expression which is necessary and sufficient to induce endoderm formation. Interestingly, sox32 is exclusive to zebrafish and works synergistically with pou5f1 to regulate its own expression and turn on sox17 expression. sox17is evolutionarily conserved from zebrafish to mouse and is necessary for endoderm formation. Signals from within the endoderm and the surrounding mesoderm specify regions in the endoderm to develop into the pancreas and other endodermal organs. Sonic hedgehog (shh) expression in the foregut establishes the anterior boundary of the pancreas primordium while cdx4 expression establishes the posterior boundary, but what regulates these factors is unclear. We determined that two Three Amino Acid Loop Extension (TALE) homeodomain transcription cofactors, Meis3 and Pbx4, regulate shh expression in the anterior endoderm. Disrupting either meis3 or pbx4 reduces shh expression in the anterior endoderm. As a result, anterior ectopic insulin expression occurs outside the normal pancreatic domain. Therefore, we discovered upstream regulatory factors of shhexpression in the anterior endoderm, which is necessary for patterning the endoderm and pancreas primordium. We performed an ENU (N-ethyl-N-nitrosurea) haploid screen to look for endocrine pancreas mutants and to find other factors involved in pancreas development and patterning. From the screen, we characterized two mutants. We identified an aldh1a2 mutant, aldh1a2um22, which blocks the production of Retinoic Acid (RA) from vitamin A. While RA is known to be necessary for differentiation of the pancreas and liver, we also found it to be necessary for intestine differentiation. Two other aldh family genes exist in the zebrafish genome, but our data suggests that aldh1a2is the only Aldh that functions in endoderm differentiation and it is maternally deposited. From the screen, we discovered a second mutant, 835.4, that spontaneously arose within the background. pou5f1 expression is normal in mutant embryos, but sox32 expression is reduced and sox17 expression is lost. Downstream endoderm genes of sox17 are also lost and as a result no endodermal organs develop. Rescue experiments indicate that the mutation is located between sox32 and sox17 in the endoderm pathway. We currently have not been successful at mapping this mutation and therefore are unable to rule out the possibility that it lies in the sox17 gene. However, our data suggest that the mutation occurs in a new gene that is necessary for sox17 expression, potentially working with sox32 and/or pou5f1.

Vesicular trafficking, the movement of vesicles between organelles and the plasma membrane for secretion, consists of multiple highly regulated processes. Many protein families function as specificity and regulatory determinants to ensure correct vesicle targeting and timing of trafficking events. The SNARE proteins dock and fuse vesicles to their target membranes. Sec1/Munc18 (SM) proteins regulate membrane fusion through interactions with the SNAREs—SM proteins have been shown to act as both inhibitors and stimulators of SNARE assembly and membrane fusion. However, the details of these SM protein functions are not understood. Constructing a model of SM protein function has been challenging due to the various modes of interactions reported between SM proteins and their SNAREs. SM proteins interact with their cognate SNAREs and SNARE complexes through several distinct modes. The most conserved mode is an interaction with the syntaxin N-peptide; other modes of binding, such as the syntaxin closed conformation, are hypothesized to be specific for specialized cell types. In order to elucidate the general function of SM proteins, I investigated the function of the endosomal SM protein Vps45p by analyzing its interactions with its cognate syntaxin Tlg2p and its role in SNARE assembly. I had two main hypotheses: that the Tlg2p N-peptide does not solely mediate the interaction between Vps45p and Tlg2p; and that Vps45p functions to stimulate SNARE complex assembly. I systematically mapped the interaction between Vps45p and Tlg2p using various Tlg2p truncations containing the different domains of Tlg2p and discovered a second binding site on Tlg2p that corresponds to the closed conformation. The neuronal SM-syntaxin pair interacts in a similar manner, indicating that this interaction mode is conserved. To characterize the closed conformation binding mode further, and determine its relationship to the N-peptide binding mode, I developed a quantitative fluorescent electrophoretic mobility shift assay. Results indicate that these two sites do not bind simultaneously and that the N-peptide binding modulates the closed conformation affinity. Furthermore, I monitored the effect of Vps45p on SNARE complex assembly using size exclusion chromatography. Under the conditions tested, Vps45p did not appear to stimulate SNARE complex assembly. The work presented here addresses several puzzling issues in the field and significantly contributes to the construction of a new mechanistic model for SM protein function. In this new model, the SM protein is recruited to the membrane by its interaction with the syntaxin N-peptide. The SM protein then binds the syntaxin closed conformation thus inhibiting SNARE complex assembly. Upon dissociation of the SM protein from the closed conformation, an event perhaps regulated by the SM protein, syntaxin opens and interacts with the other SNAREs to form a SNARE complex. Fusion ensues, stimulated by the SM protein.

It has become increasingly clear that transcription factors (TFs) play crucial roles in the development and day-to-day homeostasis that all biological systems experience. TFs target particular genes in a genome, at the appropriate place and time, to regulate their expression so as to elicit the most appropriate biological response from a cell or multicellular organism. TFs can often be grouped into families based on the presence of similar DNA binding domains, and these families are believed to have expanded and diverged throughout evolution by several rounds of gene duplication and mutation. The extent to which TFs within a family have functionally diverged, however, has remained unclear. We propose that systematic analysis of multiple aspects, or parameters, of TF functionality for entire families of TFs could provide clues as to how divergent paralogous TFs really are. We present here a multiparameter integrated network of the activity of the basic helix-loop-helix (bHLH) TFs from the nematode Caenorhabditis elegans. Our data, and the resulting network, indicate that several parameters of bHLH function contribute to their divergence and that many bHLH TFs and their associated parameters exhibit a wide range of connectivity in the network, some being uniquely associated to one another, whereas others are highly connected to multiple parameter associations. We find that 34 bHLH proteins dimerize to form 30 bHLH dimers, which are expressed in a wide range of tissues and cell types, particularly during the development of the nematode. These dimers bind to E-Box DNA sequences and E-Box-like sequences with specificity for nucleotides central to and flanking those E-Boxes and related sequences. Our integrated network is the first such network for a multicellular organism, describing the dimerization specificity, spatiotemporal expression patterns, and DNA binding specificities of an entire family of TFs. The network elucidates the state of bHLH TF divergence in C. elegans with respect to multiple functional parameters and suggests that each bHLH TF, despite many molecular similarities, is distinct from its family members. This functional distinction may indeed explain how TFs from a single family can acquire different biological functions despite descending from common genetic ancestry.

Background To investigate plasma microRNA (miRNA) profiles indicative of hepatotoxicity in the setting of lethal acetaminophen (APAP) toxicity in mice. Methods Using plasma from APAP poisoned mice, either lethally (500 mg/kg) or sublethally (150 mg/kg) dosed, we screened commercially available murine microRNA libraries (SABiosciences, Qiagen Sciences, MD) to evaluate for unique miRNA profiles between these two dosing parameters. Results We distinguished numerous, unique plasma miRNAs both up- and down-regulated in lethally compared to sublethally dosed mice. Of note, many of the greatest up- and down-regulated miRNAs, included, but were not limited to, 574-5p, 466g, 466f-3p, 375, 29c, and 148a. There was a statistically significant increase in alanine aminotransferase levels in the lethal compared to sublethal APAP dosing groups at the 12 h time point ( P < 0.001). There was 90% mortality in the lethally compared to sublethally dosed mice at the 48 h time point ( P = 0.011). Conclusion We identified unique plasma miRNAs both up- and down-regulated in lethally dosed APAP poisoned mice.