Family rivalry in the testis: Retinoblastoma protein and E2F transcription factors in testicular development and adult spermatogenesis

Disorders of male reproductive health are becoming increasingly prevalent globally. These defects, ranging from decreasing sperm counts to an increasing rate of infertility and testicular cancer, have a common origin in the early phases of testicular development, but the exact mechanisms that cause them remain unknown. Testicular development and adult spermatogenesis are complex processes in which different cell types undergo mitosis, meiosis, differentiation and apoptosis. The retinoblastoma protein family and its associated E2F transcription factors are key regulators of these cellular events. In the present study, the functions of these factors in postnatal testicular development and adult spermatogenesis were explored using different animal models. In addition, a new application of flow cytometry to study testicular cell dynamics was developed. An ablation of retinoblastoma protein in mouse Sertoli cells resulted in their cell cycle re-entry in adult testes, dedifferentiation and a severe spermatogenic defect. We showed that deregulated E2F3 contributed to these changes. Our results indicated that the E2F1 transcription factor is critical for the control of apoptosis in the developing postnatal testis. In the adult testis, E2F1 controls the maintenance of the spermatogonial stem cell pool, in addition to inhibiting apoptosis of spermatocytes. In summary, this study elucidated the complex interdependencies of the RB and E2F transcription factor families in the control of postnatal testicular development and adult spermatogenesis. Furthermore, this study provided a new methodology for the analysis of testicular cells.

Assessing development and the idea of development in the 1950s in Brazil

The decade of 1950s was a crucial period of the industrialization of the Brazilian economy. The dominant school of thought was the national-developmentalism, which was not restricted to the sphere of economic production but also encompassed political and socio-cultural processes of change. Combining repression, persuasion and paternalism, the national state took a significantly political and economic responsibility in the social, material and symbolic modernization during the Vargas and Kubitschek administrations. However, internal disputes, foreign demands and a long legacy of socio-spatial inequalities prevented the achievement of more socially inclusive goals, leading a legacy of unanswered questions that still have currency today.

Public management, policy capacity, innovation and development

In this paper we discuss the question of what factors in development policy create specific forms of policy capacity and under what circumstances developmentoriented complementarities or mismatches between the public and private sectors emerge. We argue that specific forms of policy capacity emerge from three interlinked policy choices, each fundamentally evolutionary in nature: policy choices on understanding the nature and sources of technical change and innovation; on the ways of financing economic growth, in particular technical change; and on the nature of public management to deliver and implement both previous sets of policy choices. Thus, policy capacity is not so much a continuum of abilities (from less to more), but rather a variety of modes of making policy that originate from co-evolutionary processes in capitalist development. To illustrate, we briefly reflect upon how the East Asian developmental states of the 1960s-1980s and Eastern European transition policies since the 1990s led to almost opposite institutional systems for financing, designing and managing development strategies, and how this led, through co-evolutionary processes, to different forms of policy capacity.

In search of the interrelatedness of innovation and internationalisation processes in entrepreneurial life science companies

This study is motivated by the question how resource scarce innovative entrepreneurial companies seek and leverage global resources. This study takes a resource-seeking perspective a step forward and suggests that resources that enable the entrepreneurial internationalisation are largely accrued from the early stages of entrepreneurial life; that is from the innovation development. Consequently, this study seeks to explain how innovation and internationalisation processes are interrelated in the entrepreneurial internationalisation. This main objective is approached through three research questions, (1) What role do inter-organisational relationships in innovation have in the entrepreneurial internationalisation process? (2) What kind of inward–outward links do inter-organisational relationships create in the resource-seeking-based entrepreneurial internationalisation process? (3) What kind of capability to collaborate forms in the interaction of inter-organisational relationship deployment? The research design is a mixed methods design that consists of quantitative pilot study and qualitative multiple case study of five entrepreneurial life science companies from Finland and Austria. The findings show that innovation and internationalisation processes are tightly interwoven in pre-internationalisation state. The findings also reveal that the more experienced companies are able to take advantage of complexcross-border inter-organisational relationship structures better than the starting companies. However, very minor evidence was found on inward links translating into outward links in the entrepreneurial internationalisation process, despite the expectation to observe more of these links in the data. Combined intangible-tangible resource-seeking was the most preferred to build links between inward–outward internationalisation but also to develop competence to collaborate. By adopting a resource- instead of market-seeking approach, this study illustrated that internationalisation extends to early stages of innovative companies, and that in high-technology companies’ potentially significant cross-border relationships have started to form long before incorporation. Therefore, these observations justified the firmer inclusion of pre-company history in innovative entrepreneurship studies. The study offers a conceptualisation of entrepreneurial internationalisation that is perceived as a process. The main theoretical contributions are in the areas of international entrepreneurship and in the behavioural process studies of entrepreneurial internationalisation and resource-based internationalisation. The inclusion of the innovation-based discussion, namely the innovation process, in the internationalisation process theories has clearly contributed to the understanding of entrepreneurial internationalisation in the context of international entrepreneurship. Innovation development is a central act of entrepreneurial companies, and neglecting innovation process investigation from entrepreneurial internationalisation leaves potentially influential mechanisms unexplored.

Teamwork and leadership : competitive youth soccer as a context for positive youth development

The purpose of this study was to examine processes and interactions that characterized positive developmental experiences in sport. A highly competitive and reputable U-17 girls' soccer team was chosen for the study through purposeful sampling, providing an information rich case from which data could be derived (Patton, 2002). Seventeen players and three coaches participated in this study. Based on an ethnographic methodology data were collected via observations and both informal and formal semi-structured interviews. Tlie data were coded according to the three procedures outlined by Seidel and Kelle (1995): a) noticing relevant phenomena, b) collecting examples of those phenomena, and c) analyzing those phenomena in order to find commonalities, differences, patterns and structures. Significant events and underlying themes were recounted chronologically through a collection of vignettes, aimed to provide a contextual lens for the reader. Results revolved around two prominent themes: Teamwork and leadership. These were closely related concepts that required players to demonstrate a wide range of developmental skills for the team to move collectively towards their end goal. Furthermore, teamwork and leadership experiences took both desirable and undesirable forms. For example, at the beginning of the season competition existed amongst the players at the expense of teamwork and leadership. As the season progressed the pursuit of a shared goal allowed the players to view each other as collaborators and teamwork and leadership skills became increasingly evident. At times, however, success on the field was prioritized above maintaining relationships off the field, requiring the coaches to intervene and re-establish equilibrium.

A comparison of cognitive processes and components of neurological maturation in 3-and-11 year-old children

The relationship between the child's cogni tive development and neurological maturation has been of theoretical interest for many year s. Due to diff iculties such as the lack of sophisticated techniques for measur ing neurolog ical changes and a paucity of normative data, few studies exist that have attempted to correlate the two factors. Recent theory on intellectual development has proposed that neurological maturation may be a factor in the increase of short-term memory storage space. Improved technology has allowed reliable recordings of neurolog ical maturation.. In an attempt to correlate cogni tive development and neurological maturation, this study tested 3-and II-year old children. Fine motor and gross motor short-term memory tests were used to index cogni tive development. Somatosensory evoked potentials elici ted by median nerve stimulation were used to measure the time required for the sensation to pass along the nerve to specific points on the somatosensory pathway. Times were recorded for N14, N20, and P22 interpeak latencies. Maturation of the central nervous system (brain and spinal cord) and the peripheral nervous system (outside the brain and spinal cord) was indi~ated by the recorded times. Signif icant developmental di fferences occurred between 3-and ll-year-olds in memory levels, per ipheral conduction velocity and central conduction times. Linear regression analyses showed that as age increased, memory levels increased and central conduction times decreased. Between the ll-year-old groups, there were no significant differences in central or peripheral nervous system maturation between subjects who achieved a 12 plus score on the digit span test of the WISC-R and those who scored 7 or lower on the same test. Levels achieved on the experimental gross and fine motor short-term memory tests differed significantly within the ll-year-old group.

Strategies for economic development in the Commonwealth Caribbean: a comparative study of the foreign economic policy strategies adopted by the Manley government in Jamaica and the Williams government in Trinidad and Tobago

This thesis compares the foreign economic poUcy dimension of the development strategies adopted by the governments of two Commonwealth caribbean countries: The Hardey government In Jamaica, and the· Williams government in Trlnidad and T ooago, The foreign economic policIes adopted by these governments appeared, on the surface~ to be markedly dissimilar. The Jamakan strategv on the one hand, emphasised self-reliance and national autonomy; and featured the espousal of radical oonaHgnment together with attempts to re-deftne the terms of the Islands externaa economIc relaUoos. The Trinidadian strategy 00 the other hand, featured Uberal externaUy-oriented growth poUctes, and close relatjoos with Western governments and financial institutions. Th1s study attempts to identify the explanatory factors that account for the apparent dlssimUarUy 1n the foreign economic policies of these two govemnents. The study is based on a comparison of how the structural bases of an underdeveloped ecooomYg and the foreign penetration and vulnerabUUy to external pressures asSOCiated wUh dependence, shape and influence foreign economic poUcy strategy. The framework views fore1gn ecooom1c strategy as an adaptive response on the part of the decision makers of a state to the coostralnts and opportunities provided by a particular situation. The · situat i 00' in this case being the events, conditions, structures and processes, associated wUh dependente and underdevelopment. The results indicate that the similarities and dissimHarities in the foreign economic policies of the governments of Jamaica and Trinidad were a reflecUon of the simHarities and dissimilarities in their respective situations. The conclusion derived suggests that If the foreign pol1cy field as an arena of choice, Is indeed one of opportunities and constraints for each and every state, then poHcy makers of smaU, weak, hlghW penetrated and vulnerable states enter thlS arena with constraints outweighing opportunities. This places effective limits 00 their decisional latitude and the range of policy options avaUable. Policy makers thus have to decide critical issues with few estabUshed precedents, in the face of domestic social and political cleavages, as wen as serious foreign pressures. This is a reflection not only of the trappings of dependence, but also of the Umned capabilities arising from the sman size of the state, and the Impact of the resource-gap In an underdeveloped economy. The Trinidadian strategy 1s UlustraUve of a development strategy made viable through a combination of a fortuitous circumstance, a confluence of the interests of influential groups» and accurate perception on the part of poUcy makers. These factors enabled policy makers to minimise some of the constraints of dependence. The faUure of Manlets strategy on the other hand, 15 iHustraUve of the problems involved tn the adoption of poUcles that work against the interest of internal and external political and economic forces. It is also tUustraUve of the consequences of the faUure 00 the part of policy makers to clarify goals, and to reconcile the values of rapid economic growth with increased self-reliance and national autonomy. These values tend to be mutuany Incompatible given the existing patterns of relations in the jnternational economy.

Teachers' processes of negotiating meaning of new curriculum

This qualitative study addresses the question of how teachers negotiate meaning of new curriculum to better understand how curriculum is transformed from a theoretical construct to a practical one. Through interviews with 5 teachers, their experiences were examined as they negotiated the process of implementing new curriculum. Three theoretical constructs provided the entry point into the study: epistemology, teacher knowledge, and teacher learning. Using inductive analysis, 4 points or attributes of negotiation emerged: reference, growth, autonomy, and reconciliation. These attributes provided a theoretical framework from which a constructivist conceptualization of teacher learning and teacher knowledge could serve to understand the process of how teachers negotiate meaning of curriculum. Studied and theorized in this way, teacher knowledge and teacher learning are seen to be inextricably linked in a relationship that is dynamically changed by forces of stability and instability. Theorizing the negotiation of meaning from a constructivist epistemology also strengthened the assertion that negotiating meaning is a unique structural process, and that knowledge construction is therefore unique to each knower and subject to experience in a particular time and place. The implications for such a theory are, first, that it questions the legitimacy of privatized teacher practice and, second, that it calls for a renewed conceptualization of collegial network and relationship to strengthen the capacity for negotiating meaning of curricular initiatives. Understanding the relationship of curricular theory and negotiating meaning also has implications for curriculum development. In particular, the study highlights the necessity of professional discretion and the generative process of negotiating meaning.

Exploring the Ethical Decision-Making Processes of Community Care Providers

While there has been a recent shift away from isolated, institutionalized living conditions, persons with Intellectual Disabilities (ID) may still experience restricted access to choice when it comes to making decisions about the basic aspects of their lives. A tension remains between protecting individuals from harm and promoting their right to independence and personal liberties. This tension creates complex questions and ethical concerns for care providers supporting persons with ID. This study explored the ethical decision-making processes of care providers and specifically, how care providers describe the balance of protecting supported individuals from harm while promoting their right to self-determination. Semi-structured interviews were conducted with six care providers employed by a local community agency that supports young and older adults with ID. Data were analysed using thematic analysis and broader themes were developed following phases of open and selective coding. Results indicated that care providers described ethical decision-making processes as frequent, complex, subjective, and uncomfortable. All participants described the importance of promoting independent decision-making among the individuals they support and assisting supported individuals to make informed decisions. Participants also reported work colleagues and supervisors as primary sources of information when resolving ethical concerns. This suggests that complex ethical decision-making processes are being taken seriously by care providers and supervising staff. The results of this study are well-positioned to be applied to the development of a training program for frontline care providing staff supporting individuals in community care settings.

Early Development of Auditory-Verbal and Visual-Spatial Short-Term Memory: Age and Sex Effects

Memory is a multi-component cognitive ability to retain and retrieve information presented in different modalities. Research on memory development has shown that the memory capacity and the processes improve gradually from early childhood to adolescence. Findings related to the sex-differences in memory abilities in early childhood have been inconsistent. Although previous research has demonstrated the effects of the modality of stimulus presentation (auditory versus verbal) and the type of material to be remembered (visual/spatial versus auditory/verbal) on the memory processes and memory organization, the recent research with children is rather limited. The present study is a secondary analysis of data, originally collected from 530 typically developing Turkish children and adolescents. The purpose of the present study was to examine the age-related developments and sex differences in auditory-verbal and visual-spatial short-term memory (STM) in 177 typically developing male and female children, 5 to 8 years of age. Dot-Locations and Word-Lists from the Children's Memory Scale were used to measure visual-spatial and auditory-verbal STM performances, respectively. The findings of the present study suggest age-related differences in both visual-spatial and auditory-verbal STM. Sex-differences were observed only in one visual-spatial STM subtest performance. Modality comparisons revealed age- and task-related differences between auditory-verbal and visual-spatial STM performances. There were no sex-related effects in terms of modality specific performances. Overall, the results of this study provide evidence of STM development in early childhood, and these effects were mostly independent of sex and the modality of the task.

Teaching Reading to ESL Adult Literacy Learners: The Development of an Instructor’s Handbook

The purpose of this project was to develop an instructors’ handbook that provides the declarative, procedural, and conditional knowledge associated with the interactive instructional approach, differentiated instruction, and the gradual release of responsibility framework for teaching reading to English as a second language adult literacy learners. The need for this handbook was determined by conducting a critical analysis of existing handbooks and concluding that no handbook completely addressed the 3 types of knowledge for the 3 instructional processes. A literature review was conducted to examine the nature, use, and effectiveness of the 3 instructional processes when teaching reading to ESL adult literacy learners. The literature review also examined teachers’ preferences for reading research and found that texts that were relevant, practical, and accessible were favoured. Hence, these 3 elements were incorporated as part of the handbook design. Three peer reviewers completed a 35-item 5-point Likert scale evaluation form that also included 5 open-ended questions. Their feedback about the handbook’s relevancy, practicality, accessibility, and face validity were incorporated into the final version of the handbook presented here. Reference to the handbook by ESL adult literacy instructors has the potential to support evidence-informed lesson planning which can support the ESL adult literacy learners in achieving their goals and contributing to their societies in multiple and meaningful ways.

Formation and differentiation of multiple mesenchymal lineages during lung development is regulated by {beta}-catenin signaling.

BACKGROUND: The role of ss-catenin signaling in mesodermal lineage formation and differentiation has been elusive. METHODOLOGY: To define the role of ss-catenin signaling in these processes, we used a Dermo1(Twist2)(Cre/+) line to target a floxed beta-catenin allele, throughout the embryonic mesenchyme. Strikingly, the Dermo1(Cre/+); beta-catenin(f/-) conditional Knock Out embryos largely phenocopy Pitx1(-/-)/Pitx2(-/-) double knockout embryos, suggesting that ss-catenin signaling in the mesenchyme depends mostly on the PITX family of transcription factors. We have dissected this relationship further in the developing lungs and find that mesenchymal deletion of beta-catenin differentially affects two major mesenchymal lineages. The amplification but not differentiation of Fgf10-expressing parabronchial smooth muscle progenitor cells is drastically reduced. In the angioblast-endothelial lineage, however, only differentiation into mature endothelial cells is impaired. CONCLUSION: Taken together these findings reveal a hierarchy of gene activity involving ss-catenin and PITX, as important regulators of mesenchymal cell proliferation and differentiation.

Bioethics in Health Policy Development: A Primer for Decision-Makers

Article

Role of EFNBs and EphB4 in T cell development and function

Eph kinases are the largest family of cell surface receptor tyrosine kinases. The ligands of Ephs, ephrins (EFNs), are also cell surface molecules. Ephs interact with EFNs and the receptors and ligands transmit signals in both directions, i.e., from Ephs to EFNs and from EFNs to Ephs. Ephs and EFNs are widely involved in various developmental, physiological pathophysiological processes. Our group and others have reported the roles of Ephs/EFNs in the immune system. To further investigate the function of EphBs/EFNBs in T cell development and responses, we generated EFNB1, EFNB2, EphB4 conditional gene knockout (KO) mice and EFNB1/2 double KO mice. In the projects using EFNB1 and EFNB2 knockout mice, we specifically deleted EFNB1 or EFNB2 in T cells. The mice had normal size and cellularity of the thymus and spleen as well as normal T cell subpopulations in these organs. The bone marrow progenitors from KO mice and WT mice repopulated the host lymphoid organs to similar extents. The activation and proliferation of KO T cells was comparable to that of control mice. Naïve KO CD4 cells differentiated into Th1, Th2, Th17 and Treg cells similar to naïve control CD4 cells. In EFNB2 KO mice, we observed a significant relative increase of CD4CD8 double negative thymocytes in the thymus. Flowcytometry analysis revealed that there was a moderate increase in the DN3 subpopulation in the thymus. This suggests that EFNB2 is involved in thymocyte development. Our results indicate that the functions of EFNB1 and EFNB2 in the T cell compartment could be compensated by each other or by other members of the EFN family, and that such redundancy safeguards the pivotal roles of EFNB1 and EFNB2 in T cell development and function. In the project using EFNB1/B2 double knockout (dKO) model, we revealed a novel regulatory function of EFNb1 and EFNb2 in stabilizing IL-7Rα expression on the T cell surface. IL-7 plays important roles in thymocyte development, T cell homeostasis and survival. IL-7Rα undergoes internalization upon IL-7 binding. In the dKO mice, we observed reduced IL-7Rα expression in thymocytes and T cells. Moreover, the IL-7Rα internalization was accelerated in dKO CD4 cells upon IL-7 stimulation. In T cell lymphoma cell line, EL4, over-expression of either EFNB1 or EFNB2 retarded the internalization of IL-7Rα. We further demonstrated compromised IL-7 signaling and homeostatic proliferation of dKO T cells. Mechanism study using fluorescence resonance energy transfer and immunoprecipitation demonstrated that physical interaction of EFNB1 and EFNB2 with IL-7Rα was likely responsible for the retarded IL-7Rα internalization. In the last project, using medullary thymic epithelial cell (mTEC)-specific EphB4 knockout mice, we investigated T cell development and function after EphB4 deletion in mTEC. EphB4 KO mice demonstrated normal thymic weight and cellularity. T cell development and function were not influenced by the EphB4 deletion. Lastly, the KO mice developed normal delayed type hypersensitivity. Overall, our results suggest that comprehensive cross interaction between Eph and EFN family members could compensate function of a given deleted member in the T cell development, and only simultaneous deletion of multiple EFNBs will reveal their true function in the immune system. In fact, such redundancy signifies vital roles of Ephs and EFNs in the immune system.

Development of a Phase Separation Strategy in Macrocyclization Reactions

La réaction de macrocyclisation est une transformation fondamentale en chimie organique de synthèse. Le principal défi associcé à la formation de macrocycles est la compétition inhérente avec la réaction d’oligomérisation qui mène à la formation de sousproduits indésirables. De plus, l’utilisation de conditions de dilutions élevées qui sont nécessaires afin d’obtenir une cyclisation “sélective”, sont souvent décourageantes pour les applications à l’échelle industrielle. Malgré cet intérêt pour les macrocycles, la recherche visant à développer des stratégies environnementalement bénignes, qui permettent d’utiliser des concentrations normales pour leur synthèse, sont encore rares. Cette thèse décrit le développement d’une nouvelle approche générale visant à améliorer l’efficacité des réactions de macrocyclisation en utilisant le contrôle des effets de dilution. Une stratégie de “séparation de phase” qui permet de réaliser des réactions à des concentrations plus élevées a été developpée. Elle se base sur un mélange de solvant aggrégé contrôlé par les propriétés du poly(éthylène glycol) (PEG). Des études de tension de surface, spectroscopie UV et tagging chimique ont été réalisées afin d’élucider le mécanisme de “séparation de phase”. Il est proposé que celui-ci fonctionne par diffusion lente du substrat organique vers la phase ou le catalyseur est actif. La nature du polymère co-solvant joue donc un rôle crutial dans le contrôle de l’aggrégation et de la catalyse La stratégie de “séparation de phase” a initiallement été étudiée en utilisant le couplage oxidatif d’alcynes de type Glaser-Hay co-catalysé par un complexe de cuivre et de nickel puis a été transposée à la chimie en flux continu. Elle fut ensuite appliquée à la cycloaddition d’alcynes et d’azotures catalysée par un complexe de cuivre en “batch” ainsi qu’en flux continu.