Development of human central nervous system 3D in vitro models for preclinical research

Neurological disorders are a major concern in modern societies, with increasing prevalence mainly related with the higher life expectancy. Most of the current available therapeutic options can only control and ameliorate the patients’ symptoms, often be-coming refractory over time. Therapeutic breakthroughs and advances have been hampered by the lack of accurate central nervous system (CNS) models. The develop-ment of these models allows the study of the disease onset/progression mechanisms and the preclinical evaluation of novel therapeutics. This has traditionally relied on genetically engineered animal models that often diverge considerably from the human phenotype (developmentally, anatomically and physiologically) and 2D in vitro cell models, which fail to recapitulate the characteristics of the target tissue (cell-cell and cell-matrix interactions, cell polarity). The in vitro recapitulation of CNS phenotypic and functional features requires the implementation of advanced culture strategies that enable to mimic the in vivo struc-tural and molecular complexity. Models based on differentiation of human neural stem cells (hNSC) in 3D cultures have great potential as complementary tools in preclinical research, bridging the gap between human clinical studies and animal models. This thesis aimed at the development of novel human 3D in vitro CNS models by integrat-ing agitation-based culture systems and a wide array of characterization tools. Neural differentiation of hNSC as 3D neurospheres was explored in Chapter 2. Here, it was demonstrated that human midbrain-derived neural progenitor cells from fetal origin (hmNPC) can generate complex tissue-like structures containing functional dopaminergic neurons, as well as astrocytes and oligodendrocytes. Chapter 3 focused on the development of cellular characterization assays for cell aggregates based on light-sheet fluorescence imaging systems, which resulted in increased spatial resolu-tion both for fixed samples or live imaging. The applicability of the developed human 3D cell model for preclinical research was explored in Chapter 4, evaluating the poten-tial of a viral vector candidate for gene therapy. The efficacy and safety of helper-dependent CAV-2 (hd-CAV-2) for gene delivery in human neurons was evaluated, demonstrating increased neuronal tropism, efficient transgene expression and minimal toxicity. The potential of human 3D in vitro CNS models to mimic brain functions was further addressed in Chapter 5. Exploring the use of 13C-labeled substrates and Nucle-ar Magnetic Resonance (NMR) spectroscopy tools, neural metabolic signatures were evaluated showing lineage-specific metabolic specialization and establishment of neu-ron-astrocytic shuttles upon differentiation. Chapter 6 focused on transferring the knowledge and strategies described in the previous chapters for the implementation of a scalable and robust process for the 3D differentiation of hNSC derived from human induced pluripotent stem cells (hiPSC). Here, software-controlled perfusion stirred-tank bioreactors were used as technological system to sustain cell aggregation and dif-ferentiation. The work developed in this thesis provides practical and versatile new in vitro ap-proaches to model the human brain. Furthermore, the culture strategies described herein can be further extended to other sources of neural phenotypes, including pa-tient-derived hiPSC. The combination of this 3D culture strategy with the implemented characterization methods represents a powerful complementary tool applicable in the drug discovery, toxicology and disease modeling.

How servant leadership is perceiver by leaders and followers in a Portuguese organizational context

Servant leadership theory has been the subject of great academic discussion, namely in what concerns reaching a consensus for its definition. As many frameworks have been designed in order to define the servant leader’s characteristics, we based ourselves in van Dierendonck’s review and synthesis on servant leadership (2011) to assess how it is perceived in a Portuguese organizational context. After performing several interviews in a private health care organization, we conclude that the perception of servant leadership is generally positive and that its characteristics seem to be in line with academic literature. However, some issues arose such as a seemingly lack of relevance given to authenticity and humility, the latter being a unique attribute of servant leadership. Also, we found a discrepancy between hierarchical levels’ perception of servant leadership characteristics as well as questioning if an over emphasis on service can diminish the servant leader’s impact on organizational performance.

Critical incident study on forgiveness in the organizational context

Forgiveness has been subject of interest, mainly in the psychology fields of study. Relatively to the organizational context, this topic has been somehow put aside and settled as something that is purely an intra-individual phenomenon which organizations cannot force, or even stimulate. As conflicts are common within organizations and being often difficult to overcome, eyes have turned into the role forgiveness might take in this scenario. Despite forgiveness being accepted as an intrapersonal decision and a result of predisposition as it is a result of education and culture. This study, as some already done, refuses to accept forgiveness as an unchangeable behavior that cannot be manipulated or induced by managers or by organizational context. Therefore, offering a set of incidents as well as their classification, that have been identified by individuals performing different types organizational roles in different organization which is believed as being a genuine way of delivering to the reader a set of actions and behaviors that if taken, may incentivize or inhibit forgiveness.

The characteristics of social entrepreneurship business models in Portugal

This work project is based on the MIES (Map of Innovation and Social Entrepreneurship in Portugal) database and it aims to understand the characteristics of social business models in the context of the portuguese market, by determining whether they follow the proposed characteristics by John Elkington and Pamela Hartigan, and then adding to their matrix. Furthermore, it tries to determine success patterns by comparing a group of successful social ventures with a group of less successful ones, with the objective of increasing the knowledge of social entrepreneurship as it applies to Portugal and provide a framework for future study.

Perception of organizational politics and the effect of authenticity and affective commitment on deviance and task performance in contact centers

This study aimed to understand employees’ reactions to organizational politics in Contact Centers. Drawing from a sample of 187 supervisor-employee dyads, we studied the relationship between employees’ perceptions of organizational politics and supervisor-rated task performance and deviance, and mediation effects by authenticity at work and affective commitment. Results indicate that workers tend to react to workplace politics with deviant behavior and worse task performance. We found that the relationship between perceived politics and task performance was mediated by authenticity. The relationship between perceived politics and supervisor-rated deviance was mediated by affective commitment to the organization. Implications for management are discussed.

Does companionate love express itself unequally in different organizational forms (private companies, hybrid and non-governmental organizations)?

Although, the word “Love” in organizations is seen as a rare concept, but it has gained importance in management theoretical foundation. This study seeks to explore the companionate love in distinct of organizational forms (Private companies; Social organizations; NGO and IPSS) through interviews. The results propose that it is a tensional concept with a complex dynamic: tension of personal behavior, tension of professional behavior; tension of individual impact and tension of community impact. The love dynamic has common points to all organizations, but its expression depends on the specific form of the organization.