The challenge of vector development in gene therapy

Gene therapy is the treatment of diseases based on the transfer of genetic information. Agents that carry or deliver DNA to target cells are called vectors (Latin vector: carrier, deliverer). Ideally, a vector should accommodate an unlimited amount of inserted DNA, lack the ability of autonomous replication of its own DNA, be easily manufactured, and be available in concentrated form. Secondly, it should have the ability to target specific cell types or to limit its gene expression to specific cell types, and to achieve sustained gene expression in the long term or in a controlled fashion. Finally, it should not be toxic or immunogenic. Such a vector does not exist and none of the DNA delivery systems so far available for in vivo gene transfer is perfect with respect to any of these points. Gene therapy and the means to promote it depend heavily on the development and improvement of new gene vector systems.

Customer involvement in lean startup principles: case of game development studio

The objective of this thesis is to better understand customer’s role in lean startup methodology. The aim is to find out how customers are involved in lean startup methodology implantation and increase the likelihood of new venture survival. This study emphasizes the usage of customers in shaping of new product development processes within companies, through iteration and constant communication. This communication facilitates the development of features that are requested by the customers and enhances the prospects of the new venture. The empirical part of the study is a single qualitative case study that uses action research to implement the lean startup methodology into a pre-revenue venture and examines its customer involvement processes. The studied case company is Karaoke d.o.o., developing a game called kParty. The study used the theory discussed in the literature review: customer involvement (in the survey and interviews conducted for the lean startup methodology), lean principles (through the implementation of lean startup methodology) and lean startup methodology, which are the central building parts of this thesis as a whole. The thesis contributes to the understanding of customer involvement in lean startup methodology, while giving practical implications of customer orientation and product market fitting.

The novel p.E89K mutation in the SRY gene inhibits DNA binding and causes the 46,XY disorder of sex development

Male sex determination in humans is controlled by the SRY gene, which encodes a transcriptional regulator containing a conserved high mobility group box domain (HMG-box) required for DNA binding. Mutations in the SRY HMG-box affect protein function, causing sex reversal phenotypes. In the present study, we describe a 19-year-old female presenting 46,XY karyotype with hypogonadism and primary amenorrhea that led to the diagnosis of 46,XY complete gonadal dysgenesis. The novel p.E89K missense mutation in the SRY HMG-box was identified as a de novo mutation. Electrophoretic mobility shift assays showed that p.E89K almost completely abolished SRY DNA-binding activity, suggesting that it is the cause of SRY function impairment. In addition, we report the occurrence of the p.G95R mutation in a 46,XY female with complete gonadal dysgenesis. According to the three-dimensional structure of the human SRY HMG-box, the substitution of the conserved glutamic acid residue by the basic lysine at position 89 introduces an extra positive charge adjacent to and between the positively charged residues R86 and K92, important for stabilizing the HMG-box helix 2 with DNA. Thus, we propose that an electrostatic repulsion caused by the proximity of these positive charges could destabilize the tip of helix 2, abrogating DNA interaction.

Acute exposure to lead increases myocardial contractility independent of hypertension development

We studied the effects of the acute administration of small doses of lead over time on hemodynamic parameters in anesthetized rats to determine if myocardial contractility changes are dependent or not on the development of hypertension. Male Wistar rats received 320 µg/kg lead acetateiv once, and their hemodynamic parameters were measured for 2 h. Cardiac contractility was evaluated in vitro using left ventricular papillary muscles as were Na+,K+-ATPase and myosin Ca2+-ATPase activities. Lead increased left- (control: 112 ± 3.7 vs lead: 129 ± 3.2 mmHg) and right-ventricular systolic pressures (control: 28 ± 1.2vs lead: 34 ± 1.2 mmHg) significantly without modifying heart rate. Papillary muscles were exposed to 8 µM lead acetate and evaluated 60 min later. Isometric contractions increased (control: 0.546 ± 0.07 vs lead: 0.608 ± 0.06 g/mg) and time to peak tension decreased (control: 268 ± 13vs lead: 227 ± 5.58 ms), but relaxation time was unchanged. Post-pause potentiation was similar between groups (n = 6 per group), suggesting no change in sarcoplasmic reticulum activity, evaluated indirectly by this protocol. After 1-h exposure to lead acetate, the papillary muscles became hyperactive in response to a β-adrenergic agonist (10 µM isoproterenol). In addition, post-rest contractions decreased, suggesting a reduction in sarcolemmal calcium influx. The heart samples treated with 8 µM lead acetate presented increased Na+,K+-ATPase (approximately 140%, P < 0.05 for control vs lead) and myosin ATPase (approximately 30%, P < 0.05 for control vs lead) activity. Our results indicated that acute exposure to low lead concentrations produces direct positive inotropic and lusitropic effects on myocardial contractility and increases the right and left ventricular systolic pressure, thus potentially contributing to the early development of hypertension.

Climate Change and Ethics of Geoengineering -- Implications Of Climate Emergency Ethics

Global climate change and intentional climate modification, i.e. geoengineering include various ethical problems which are entangled as a complex ensemble of questions regarding the future of the biosphere. The possibilities of catastrophic effects of climate change which are also called “climate emergency” have led to the emergence of the idea of modifying the atmospheric conditions in the form of geoengineering. The novel issue of weather ethics is a subdivision of climate ethics, and it is interested in ethical and political questions surrounding weather and climate control and modification in a restricted spatio-temporal scale. The objective of geoengineering is to counterbalance the adverse effects of climate change and its diverse corollaries in various ways on a large scale. The claim of this dissertation is that there are ethical justifications to claim that currently large-scale interventions to the climate system are ethically questionable. The justification to pursue geoengineering on the basis of considering its pros and cons, is inadequate. Moral judgement can still be elaborated in cases where decisions have to be made urgently and the selection of desirable choices is severely limited. The changes needed to avoid severe negative impacts of climate change requires commitment to mitigation as well as social changes because technical solutions cannot address the issue of climate change altogether. The quantitative emphasis of consumerism should shift to qualitative focus on the aspiration for simplicity in order to a move towards the objective of the continuation of the existence of humankind and a flourishing, vital biosphere.

RR soybean seed quality after application of glyphosate in different stages of crop development

In consequence of several studies and speculations concerning the issue of RR transgenic soybean after the application of glyphosate, additional scientific investigations became necessary to clarify the actual viability of the product use when applied in different developmental stages of the soybean crop. Therefore, this study was aimed to evaluate the physiological quality as well as seed health quality of RR soybean subjected to application of the herbicide glyphosate in different phonological stages of the transgenic soybean, cultivar CD 219RR. For this, an experiment with a complete block experimental design with treatments randomly distributed within the block, with four replications, was carried out. The assessed treatments were foliar sprayings of glyphosate in three increasing dosages [0 (control); 1,440 g ha-1; and 2,880 g ha-1] of acid equivalent, applied in two crop developmental stages: vegetative (V6) and reproductive (R2). The variables assessed were: germination; first count of germination; fresh and dry mass of seedlings, lengths of seedling and root; vigor and viability by the tetrazolium test; and seed health quality. Glyphosate application may adversely affect physiological quality of RR soybean seeds, when applied in dosages varying from 1,440 to 2,880 g acid equivalent per hectare at the stages V6 and R2.

Construing social dimensions of personality development: nurses as educators

A convenience sample of twenty registered nurses was recruited from two' general hospitals and two community college nursing schools. Kelly's (1955) Personal Construct Theory provided the theoretical framework to discover how nurses perceived themselves as educators. The nurses completed a self-administered Self-Perception Inventory (Soares, 1983) to determine their perception of self as nurse and ideal self as nurse. In an interview, each of the nurses constructed a rank-order repertory grid adapted from Kelly's (1955) Role Repertory Construct Test. Twelve constructs derived from the Self-Perception Inventory (Soares, 1983) were ranked according to a list of ten elements common to a teaching situation. Rank order correlations among the constructs were determined with Spearman's rho. Using a dependent samples t-test, significant differences were found between perceptions of current and ideal self for staff nurses. Significant differences were also found between nurse educators' perceptions of self and ideal self as nurse. No significant differences were determined in perceptions of self as nurse and ideal self as nurse between the staff nurse and nurse educator groups with an independent samples t-test. However, observations of single constructs revealed that although several constructs are shared between the groups in the perception of self in a teaching situation, both groups hold constructs that operate exclusively in their separate domains. The nature and strength of the relationships between the common and unique constructs are different for each group. Nurses I self-perceptions appear to be influenced by the historical development of nursing, role socialization during nursing education, social expectations and gender issues in the health care system.

Identification and description of the development of the relationships between mentor and mentee teachers in the Halton Board of Education "Partners in the Classroom" Program

Fifteen mentoring pairs of teachers were randomly selected from each group of teachers that had participated in the Halton Board of Education "Partners in the Classroom" program during 1988/89, 1989/90, and 1990/91. Each teacher was personally interviewed. Interviews were recorded, transcriptions were prepared and examined and analyzed. During the first part of the interview questions were asked regarding personal and professional demographics. The purpose of the second part of the interview was to gain information relating to the development of the relationships, over a three-year period, between mentor and mentee teacher participants in the "Partners in the Classroom" program. The analysis of the data suggest that there are identifiable changes in the development of the relationship between the mentor teacher and the mentee teacher over time. Implications from the study results that could enhance the induction program for new teachers are discussed.

Utilitarianism and Buddist ethics: a comparative approach to the ethics of animal research

This thesis explores the comparison utilitarianism and Buddhist ethics as they can be applied to animal research. It begins by examining some of the general discussions surrounding the use of animals in research. The historical views on the moral status of animals, the debate surrounding their use in animals, as well as the current 3R paradigm and its application in Canadian research are explored. The thesis then moves on to expound the moral system of utilitarianism as put forth by Jeremy Bentham and John Stuart Mill, as well as contemporary additions to the system. It also looks at the basics of Buddhist ethics well distinguishing the Mahayana from the Therevada. Three case studies in animal research are used to explore how both systems can be applied to animal research. It then offers a comparison as to how both ethical systems function within the field of animal research and explores the implications in their application on its practice.

Towards a just community: an examination of the development of cultural citizenship rights in Canada from a communitarian perspective

The notion of citizenship, while a basic human right, has come under scrutiny. It was once assumed a liberal inspired regime of citizenship rights would reign as the primary ideological perspective in the Western world, however this has not been the case. Numerous competing paradigms have questioned the premise upon which liberal guarantees of citizenship rights are based. In particular, communitarianism has subjected liberal rights discourse to a closer examination. Communitarian theory holds that universalist principles negate any articulation of community and its internal diversity, such as cultural citizenship. It is this understanding of citizenship that has taken hold in Canada. The Canadian political experience illustrates a number of attributes associated with communitarian thought. It is a collectivist society that articulates a notion of the common good, acknowledges the internal diversity of its citizens and possesses a highly developed deliberative democratic process. To this end, Canada can be described as being more communitarian than liberal in nature in the process it has adopted to address citizenship rights. However, the type of commuIiitarianism displayed in Canada differs from the political models examined by such scholars as Michael Sandel, Iris Marion Young or Will Kymlicka. Cultural citizenship rights are fluid and malleable in Canada. While no clear guarantees of citizenship rights exist, there is a common commitment by Canadians to engage in a fair, open and inclusive deliberative process. This model is unique to Canada; it cannot be exported in that it is a product of Canadian political culture. As a result, the contemporary demands of cultural citizenship are dealt with effectively and democratically in Canada in that the proper mechanisms for public deliberation exist.

Creating a global consciousness throught the driver model of curriculum development

The purpose of this study was to investigate the effect a human link through the One World Youth Project has on a global education program, if a human connection through the program enhances a student's ability to develop a critical consciousness of global issues, and the etTectiveness of thc constructivist-based Driver Model of Curriculum Development, which served as the curriculum model in this study. An action based research cycle was chosen as this study's research methodology and incorporated 5 qualitative data collection instruments: a) interviews and questionnaires, b) artifacts, c) teacher journal, d) critical friend's observation forms, and e) my critical friend's postobservation interviews. The data were conected from 4 student participants and my critical friend during all stages of the action research cycle. The results of this study provide educators with data on the impact of human connections in a global education program, the effects these connections have on students, and the effectiveness of the Driver Model of Curriculum Development. This study also provides practical activities and strategies that could be used by educators to develop their own global education programs. The United Nations drafted the Millennium Development Goals in an effort to improve the lives of billions of people across the globe. The eight goals were developed with the support of all member nations since all human beings are global citizens who have a responsibility to make the world a better place. Students need to develop a critical consciousness of global issues so that they can work with others to eliminate them. Students who are taught to restate the opinions of others win not be prepared to inherit a world full of challenges that will require new innovative ideas to foster positive change.

Competing and Conflicting Land Uses at the Rural-Urban Interface: Understanding the Impacts of Residential Development on Agricultural Landscapes

Rural communities are currently undergoing rapid restructuring as globalization impacts the future viability of many small towns. Agricultural regions throughout Canada, in particular, Niagara-on-the-Lake, are forced to adapt to changes within the industry. In addition to these challenges, sprawling residential developments from nearby urban centres are changing the dynamic of this town, resulting in conflicts between the residential and agricultural land uses. This thesis explores these conflicts from the perspective of the residents and the farmers. It was found that the initial sources of conflict related to noise-generating farm activities are no longer a concern, while the use of pesticide have become a source of contention among the residents. The farmers, alternately, were found to be proactive and strived to limit the potential for conflict with adjacent residents. Lastly, it was determined that planning legislation aggravates land use conflicts within Niagara-on-the-Lake and need to better address these land use conflicts.

An Examination of the Development of Online Higher Education in Canada and China: Keeping Pace and Making Space

This study examined the similarities and differences that currently exist between Chinese and Canadian online higher education, and explored the economic, political, and sociocultural environments that have shaped online education in these two jurisdictions. Furthermore, this paper discussed the efficacy of, and potential for, future development of online learning in higher education in both Canada and China. The research employed a collective case study design to gather information and data on the development of online higher education. The analysis on Contact North in Canada and the One-Man University in China provide a comparative perspective on the development of 2 typical online higher educational institutions in these two countries. The study revealed that the development of online higher education is influenced by the economic, political, and sociocultural factors of environment. Contact North and the One-Man University share similarities in many aspects, but are characteristically different. The Contact North can set an example for establishing and operating a self-regulated MOOCs platform. The study also generated implications for both organizations.

Youth engagement: the ethics of inclusion and exclusion

This study focuses on the engagement of children and youth in their communities and the ways they are included in and excluded from community life. Using a content analysis of a small town United States newspaper over a one-year period, examples of engagement were identified and classified into 12 categories: programs, clubs and special events; fundraising and community service; business and community support; participation in community events; school events; athletic and other performances; employment; involvement in local planning and decision making; serving as a community representative; visibility and recognition; criminal activity and accidents; and use of public space. Examples of community exclusion were identified as well. Young people were engaged primarily through activities that were adult-directed or supervised, or organized through schools, churches, and youth clubs. There was little involvement in local planning, decision making, or activism. Some evidence existed of peer teaching, leadership, and self-initiated activities, as well as intentional efforts by adults to give youth a greater voice in community activities. Implications include several ethical issues regarding the role of young people in community life, particularly young children, and the need for greater awareness on the part of communities of the contributions young people can make.