The design and synthesis of novel APIs based upon topiramate

EngDThe research project, conducted in collaboration with Onyx Scientific Limited and Newcastle University, is focused on the anti-convulsant drug topiramate that is best known as a treatment for epilepsy. The established data on the efficacy and limitations of topiramate highlighted it as a promising drug candidate for reprofiling, repurposing or modification. The interest in topiramate stems primarily from its multi-factorial mode of biological action that results in a complex combination of pharmacological effects. This is manifested by the drug having a complex side effects profile with the most common being related to the central nervous system, weight loss and gastrointestinal disorders. The drug influences the activity of a number of in vivo sites including certain types of voltage activated sodium and calcium ion channels, AMPA glutamate receptors and particular isozymes of the enzyme carbonic anhydrase (CA). Of particular interest to this work is the specific inhibition of mitochondrial CAs, CAVA and CAVB by topiramate. The inhibition of these mitochondrial CAs is thought to contribute to the weight loss effects observed in patients being treated with topiramate. The project aims to develop novel selective CA inhibitors (CAIs) that have inhibitory properties towards only particular and relevant CAs. It is hoped that this will enable the pharmacological activity of topiramate to be optimised and certain of its aspects positively exploited whilst limiting toxicity and off-target biological effects. The objective of the project is to identify potential new APIs by assessing the biological activity of known derivatives of topiramate on the CA targets of interest and by creating novel molecules that introduce structural modifications to topiramate that may increase the specificity for certain CAs and vary the drug’s pharmacological effects. The approach of the project is to undertake a classical drug design cycle using modern drug discovery techniques. In silico models were used to identify compounds, both known and novel, which show promising interactions with one or more of the target active sites and which therefore may demonstrate a selective biological response. The in silico hits generated from modelling will be the primary synthetic targets and are the focus of this research

Developing an assessed reading portfolio to improve reading habits and raise test results

For over 10 years, preparatory students at Khalifa University, UAE, have been encouraged to improve their reading and language learning skills through the use of an assessed reading portfolio. This paper briefly outlines the rationale behind this type of assessment and the design features of the portfolio, before detailing some of the many adaptations that it has experienced over the years, paying particular attention to recent developments involving the use of technology. Through an evaluation of the portfolio, using authentic scores for the portfolio and comparing them to IELTS reading test scores, it emerges that students who do well on the portfolio are more likely to make gains in their reading scores than those who do not perform well in their reading portfolio assessment

Native American Students’ Understandings of Geologic Time Scale: 4-8th Grade Students’ Understandings of Earth's Geologic History

AbstractGeologic time scales is very important concept for understanding earth system events such as global climate change. However, understanding of geologic time scale in a relationship with human history is very difficult because of relatively short period of human existence in earth history. This study shows that Native American elementary students understand geological and historical event based on relative order of earth history. They understand Earth's geological event as a sequential series. More importantly, they understand human history based on their own culture and history

Developing Environmental Law for All Citizens

On 20 May 2002, Timor-Leste became a country. Its Constitution, which came into force on 20 May 2002, is based on civil law, with many similarities to Portugal\u27s legal system. The Constitution also laid the foundation for environmental law, which the government has been developing ever since. This overview of the development of environmental law in Timor-Leste describes the constitutional provisions that are the source of environmental law in the country; presents the policy basis for environmental law; reviews the legal instruments governing the environment that the government has adopted since 2002; introduces draft laws under consideration at the end of 2014; and highlights the initiative of the Ministry of Justice\u27s Legal Training Center to teach national environmental law to the legal professionals who will be the country\u27s future judges, prosecutors and public defenders

Developing Environmental Law for All Citizens

On 20 May 2002, Timor-Leste became a country. Its Constitution, which came into force on 20 May 2002, is based on civil law, with many similarities to Portugal\u27s legal system. The Constitution also laid the foundation for environmental law, which the government has been developing ever since. This overview of the development of environmental law in Timor-Leste describes the constitutional provisions that are the source of environmental law in the country; presents the policy basis for environmental law; reviews the legal instruments governing the environment that the government has adopted since 2002; introduces draft laws under consideration at the end of 2014; and highlights the initiative of the Ministry of Justice\u27s Legal Training Center to teach national environmental law to the legal professionals who will be the country\u27s future judges, prosecutors and public defenders

Teachers' and children's personal epistemologies for moral education: Case studies in early years elementary education

While there is strong interest in teaching values in Australia and internationally there is little focus on young children’s moral values learning in the classroom. Research shows that personal epistemology influences teaching and learning in a range of education contexts, including moral education. This study examines relationships between personal epistemologies (children’s and teachers’), pedagogies, and school contexts for moral learning in two early years classrooms. Interviews with teachers and children and analysis of school policy revealed clear patterns of personal epistemologies and pedagogies within each school. A whole school approach to understanding personal epistemologies and practice for moral values learning is suggested

Improving young people’s health and wellbeing through a school health research network: reflections on school-researcher engagement at the national level

The School Health Research Network is a policy-practice-research partnership established in Wales in 2013. The Network aims to: provide health and wellbeing data for national, regional and local stakeholders, including schools; co-produce school-based health improvement research for Wales; and build capacity for evidence-informed practice in the school health community. School-focused engagement activities include providing member schools with bespoke Student Health and Wellbeing Reports, hosting school health webinars, producing school-friendly research briefings, and holding annual events for schools. The Network’s model for co-producing research with schools is described and its impacts on schools is explored. These include more efficient recruitment of schools to research projects, school involvement in intervention development, schools beginning to embed evidence-informed practice by using their Reports and other Network resources, and securing funding to evaluate innovative health and wellbeing practices identified by schools. Drawing on the Trans-disciplinary Action Research (TDAR) literature, the article reflects on how TDAR principles have underpinned Network progress. The concept of reciprocity in the co-production literature and its relevance to engagement with schools is also explored, along with the Network’s contribution to our understanding of how we can build sustainable co-production at large scale in order to generate national level action and benefit

The potential yield of active play in the prevention of cancer

Literature has shown that participation in physical activity is associated with a reduction in the incidence of certain cancers. Physical activity levels across the life course are low. Since cellular damage from an inactive lifestyle accumulates over time, promoting physical activity from childhood is fundamental for cancer prevention. To date, interventions to promote physical activity in children have been unsuccessful over the long term. Physical activity can be accrued through several domains including sport and active play. Research suggests that sport participation and not active play tracks from childhood to adulthood. Active play is easier to promote because it does not necessitate a certain level of skill or competency, and is enjoyable. The purpose of the present paper is to encourage more research into all areas of active play to increase population physical activity levels across the life course and thus aid in the prevention of specific cancers

Usability, Acceptability, and Effectiveness of Web-Based Conversational Agents to Facilitate Problem Solving in Older Adults: Controlled Study.

BACKGROUND: The usability and effectiveness of conversational agents (chatbots) that deliver psychological therapies is under-researched. OBJECTIVE: This study aimed to compare the system usability, acceptability, and effectiveness in older adults of 2 Web-based conversational agents that differ in theoretical orientation and approach. METHODS: In a randomized study, 112 older adults were allocated to 1 of the following 2 fully automated interventions: Manage Your Life Online (MYLO; ie, a chatbot that mimics a therapist using a method of levels approach) and ELIZA (a chatbot that mimics a therapist using a humanistic counseling approach). The primary outcome was problem distress and resolution, with secondary outcome measures of system usability and clinical outcome. RESULTS: MYLO participants spent significantly longer interacting with the conversational agent. Posthoc tests indicated that MYLO participants had significantly lower problem distress at follow-up. There were no differences between MYLO and ELIZA in terms of problem resolution. MYLO was rated as significantly more helpful and likely to be used again. System usability of both the conversational agents was associated with helpfulness of the agents and the willingness of the participants to reuse. Adherence was high. A total of 12% (7/59) of the MYLO group did not carry out their conversation with the chatbot. CONCLUSIONS: Controlled studies of chatbots need to be conducted in clinical populations across different age groups. The potential integration of chatbots into psychological care in routine services is discussed