Genetic Loci Contributing to Spontaneous Autoimmune Diabetes

Background and Aims: Spontaneous type 1 diabetes (T1D) in the BioBreeding (BB) rat mimics human T1D as the rats experience weight loss, polydipsia, polyuria, ketoacidosis, onset during puberty and insulin-dependency within a day after diagnosis. Because the DP rat develops T1D spontaneously, it is a prime laboratory animal for dissecting the genetics of T1D susceptibility without the need for external manipulation. The BB rat is comprised of two separate substrains; the diabetes prone (BBDP) and the diabetes resistant (BBDR). Failure to express the Gimap5 protein is associated with lymphopenia (lyp) and linked to T1D in the BBDP rat. In an intercross between F1(BBDP x F344) rats we identified a rat with a recombination event on rat chromosome (RNO) 4, allowing us to fix 34Mb of F344 between D4Rat253 and D4Rhw6 in the congenic DR.lyp rat line with two Mb of BBDP DNA, encompassing the Gimap5 mutation, introgressed on the DR genetic background. The aim of this thesis was to characterize the F344 DNA introgression, test the hypothesis that the introgression would result in 1) no effect on T1D development or 2) protection from T1D, generate congenic sublines and positionally clone and characterize the resulting candidate genes on rat RNO4. Material and Methods: The F344 fragment in the DRF.f/f rat line was fixed onto the DR.lyp background in a total of nine backcross and seven intercross matings. To generate DRF.f/f congenic sublines, DRF.f/f rats were crossed to inbred BBDR or DR.lyp/lyp rats and the offspring genotyped, phenotyped for lymphopenia and monitored for T1D. Positional candidate genes were then subjected to coding sequence analysis, cDNA sequencing and/or quantitative real-time (qRT) PCR expression analysis. Results: DRF.f/f rats, homozygous for the F344 allele, were lymphopenic but did not develop T1D while all (100%) DR.lyp/lyp rats developed T1D by 83 days of age. Generation of congenic sublines revealed that reduction of the DRF.f/f F344 DNA fragment by 26 Mb (42.52 Mb-68.51 Mb) retained complete T1D protection. Further dissection revealed that a 2 Mb interval of F344 DNA (67.41-70.17 Mb) (Iddm38) resulted in 47% protection while retaining <1 Mb of F344 DNA at the distal end (Iddm39) resulted in 28% protection, both of which significantly delayed onset. Comparative analysis of T1D frequency in the DRF.f/f congenic sublines refined the Iddm38 and Iddm39 intervals to approximately 670 Kb between SNP SS105325016 and D4Rat26 and 340 Kb proximal to Gimap5, respectively. Coding sequence analysis revealed TCR Vβ 8E, 12 and 13 as candidate genes in Iddm38 and Znf467 and Atp6v0e2 in Iddm39. Quantitative RT-PCR analysis of whole organ as well as in FACS sorted thymocytes and peripheral T-cells stained with CD4 and CD8 monoclonal antibodies showed a reduction in expression of four out of five Gimap genes located within the Iddm39 interval, in addition to Gimap5, in DR.lyp/lyp spleen and mesenteric lymph nodes (MLN) when compared to DR.+/+. Conclusions: Our data demonstrates that introgression of a 34 Mb region of the F344 genome, proximal to the mutated Gimap5 gene, renders the congenic DR.lyp/lyp rat T1D resistant despite being lymphopenic. Generation of congenic sublines revealed that spontaneous T1D in the BB rat is controlled, in part, by at least two genetic loci, Iddm38 and Iddm39, in addition to the Gimap5 mutation on RNO4. Coding sequence analysis revealed TCR Vβ 8E, 12 and 13 as candidate genes in Iddm38 and Znf467 and Atp6v0e2 as candidate genes in Iddm39. Quantitative RT-PCR expression analysis suggests that the lack of the Gimap5 protein in the DR.lyp/lyp congenic rat impairs expression of the entire Gimap gene family and regulates T-cell homeostasis in the peripheral lymphoid organs. The molecular identification and characterization of the genetic factors protecting from T1D in the DRF.f/f congenic rat line should prove critical to disclose the mechanisms by which T1D develops in the BB rat

New roles for Fc receptors in neurodegeneration-the impact on immunotherapy for Alzheimer's disease

There are an estimated 18 million Alzheimer's disease (AD) sufferers worldwide and with no disease modifying treatment currently available, development of new therapies represents an enormous unmet clinical need. AD is characterized by episodic memory loss followed by severe cognitive decline and is associated with many neuropathological changes. AD is characterized by deposits of amyloid beta (A?), neurofibrillary tangles, and neuroinflammation. Active immunization or passive immunization against A? leads to the clearance of deposits in transgenic mice expressing human A?. This clearance is associated with reversal of associated cognitive deficits, but these results have not translated to humans, with both active and passive immunotherapy failing to improve memory loss. One explanation for these observations is that certain anti-A? antibodies mediate damage to the cerebral vasculature limiting the top dose and potentially reducing efficacy. Fc gamma receptors (Fc?R) are a family of immunoglobulin-like receptors which bind to the Fc portion of IgG, and mediate the response of effector cells to immune complexes. Data from both mouse and human studies suggest that cross-linking Fc?R by therapeutic antibodies and the subsequent pro-inflammatory response mediates the vascular side effects seen following immunotherapy. Increasing evidence is emerging that Fc?R expression on CNS resident cells, including microglia and neurons, is increased during aging and functionally involved in the pathogenesis of age-related neurodegenerative diseases. Therefore, we propose that increased expression and ligation of Fc?R in the CNS, either by endogenous IgG or therapeutic antibodies, has the potential to induce vascular damage and exacerbate neurodegeneration. To produce safe and effective immunotherapies for AD and other neurodegenerative diseases it will be vital to understand the role of Fc?R in the healthy and diseased brain. Here we review the literature on Fc?R expression, function and proposed roles in multiple age-related neurological diseases. Lessons can be learnt from therapeutic antibodies used for the treatment of cancer where antibodies have been engineered for optimal efficacy

Localizing the United Nations Sustainable Development Goals in northern Norway: Transdisciplinary approaches for sustainable coastal development

I 2015 lanserte FN «2030 Agenda for Sustainable Development» med et unikt og ambisiøst rammeverk for global bærekraft som inkluderer 17 bærekraftsmål (SDG). Siden den gang har mange ledere over hele verden på lokalt, regionalt og nasjonalt nivå fortsatt å kjempe med utfordringen å lokalisere bærekraft. Hvordan går vi fra globalt til lokalt nivå? Til tross for mangfoldet av internasjonale retningslinjer for selve bærekraftsmålene, utdyper ikke litteraturen hvordan bærekraftsmålene kan implementeres på nasjonalt nivå, eller hvordan de kan integreres gjennom regionale og lokale styringsnivåer. Dette er en utfordring for FN-medlemmer, inkludert i Norge, som må forene sin bærekraftspolitikk med den globale agendaen. I denne doktorgraden har jeg undersøkt hvordan jeg kan lokalisere bærekraftsmålene i en kommune i Nord-Norge på måter som er legitime, fremtredende og troverdige og som kan føre til sosiale transformasjoner for global bærekraft og bærekraftig utvikling for fremtidige generasjoners velstand og velferd. Integrering og operasjonalisering av bærekraftsmålene via bærekraftig utviklingspolitikk er avgjørende for å nå målene og videre for å kunne implementere langsiktige bærekraftstransformasjoner. Slik operasjonalisering bør ta form av en lokaliseringsprosess som forankrer bærekraftmålene til kontekst på grasrotsnivå og integrerer behovene, prioriteringene og verdiene til individer i lokalsamfunnene (som må følge retningslinjene). For å oppnå dette, foreslår jeg en vei for å muliggjøre transformativ endring for bærekraft som overskrider individ, kultur, teknologi, politikk og det naturlige miljøet til sosial-økologiske systemer. Gjennom doktorgradsavhandlingen utforsket jeg denne SDG-lokaliseringsprosessen ved å bruke en transdisiplinær tilnærming til bærekraftsstudier som bygger på prinsipper for post-normal vitenskap og de «Tre Sfærene for Transformasjon» for bærekraft. Jeg brukte etablerte forskningsmetoder og analytiske rammeverk fra samfunnsvitenskapene (Social Network Analysis og Q-methodology) for å undersøke hvordan SDGene kunne forankres i en lokal kontekst og tilpasses lokale behov. Samtidig tilstrebet jeg å oppnå integritet og relevans for det globale målet om bærekraftig utvikling. Tre hovedspørsmål for å utforske denne SDG-lokaliseringsprosessen ble utviklet: (1) Hvordan kan kunnskap og informasjon spores innenfor en multi-sektor og mega-organisatorisk institusjon?; (2) Hva er den lokale diskursen om bærekraftig kystutvikling i Nord-Norge og hvordan informerer eller legger denne kunnskapen til rette for SDG-lokalisering?; og (3) Hvordan illustrerer SDG-lokaliseringsprosessen «fractal agency» for sosial transformasjon? I avhandlingen demonstrerer jeg først at den strukturelle og sosiale kompleksiteten til et institusjonelt nettverk påvirker deling av kunnskap og informasjon. Imidlertid danner de individuelle menneskelige forbindelsene og felles mål innenfor dette nettverket grunnlaget for institusjonell sammenheng, funksjonalitet og effektivitet. Jeg har også belyst de individuelle perspektivene på bærekraftig kystutvikling slik de kommer til uttrykk i Andøy kommune og vist hvordan felles perspektiver som kommer frem fra lokalsamfunnet kan tjene som utgangspunkt for flersektorielt samarbeid og diskusjon. Til slutt konkluderer jeg med at for å sikre at SDG-lokaliseringsprosessen muliggjør sosiale transformasjoner for bærekraft, må individuell kapasitet aktiveres og oppmuntres gjennom deltakende prosesser og interessentengasjement som styrker sosial «agency» på måter som er selvopprettholdende og overskrider lokal, regional og nasjonal kontekster. Bærekraftsmålene og bærekraftig utviklingspolitikk er komplekse. De må stimulere transformativ endring på tvers av politiske, praktiske og personlige sfærer ved å være forankret i universelle verdier som gjelder for alle mennesker. Jeg presenterer en SDG-lokaliseringsprosess basert på prinsipper om vitenskapelig kvalitet og troverdighet, myndighetslegitimitet og gjenspeiling av lokale og nasjonale behov. Denne unike tilnærmingen gir en ansvarlig, innovativ og pålitelig vei videre for integrering av de globale målene for bærekraft i lokalsamfunnene.In 2015, the United Nations launched the “2030 Agenda for Sustainable Development” with a unique and ambitious framework for global sustainability that includes a framework of the 17 Sustainable Development Goals (SDGs). Since then, many leaders worldwide at the community, regional and national levels continue to grapple with the challenge of localizing sustainability. How do we go from global to local? Despite the variety of international guidelines on the SDGs themselves, the literature does not elaborate on how the SDGs should be implemented at the national level nor how they should be integrated through regional and local levels of governance. This is a challenge for United Nations members, including Norway, that must reconcile their sustainability policies to the global agenda. In this PhD, I have examined how the SDGs can be localized in the case study area in northern coastal Norway in ways that are legitimate, salient, and credible, leading to social transformations for global sustainability and sustainable development for the prosperity and wellbeing of future generations. The integration and operationalization of the SDGs via sustainable development policy is crucial for the achievement of the goals and for long-term sustainability transformations. Such operationalization should take the form of a localization process that anchors the SDGs to on-the-ground contexts and integrates the needs, priorities, and values of individuals in the local communities who must abide by the policies. Through this PhD thesis, I explored this SDG localization process using a transdisciplinary approach to sustainability studies that drew on principles of Post-Normal Science and made use of the Three Spheres of Transformation for Sustainability framework. I applied established research methods and analytical frameworks from the social sciences (Social Network Analysis and Q-methodology) to investigate how the SDGs could be anchored to a local context and adapted to local needs, while maintaining integrity and relevance to the global aim of sustainable development worldwide. Three main questions emerged to explore the SDG localization process: (1) How can knowledge and information be tracked within a multi-sector and mega-organizational institution?; (2) What is the local discourse on sustainable coastal development in northern coastal Norway and how does this knowledge inform or facilitate SDG localization?; and (3) How does the SDG localization process illustrate fractal agency for social transformation? Through this thesis I first demonstrate that the structural and social complexity of an institutional network affects the sharing of knowledge and information. However, the individual human connections and shared goals within that network form the basis for institutional coherence, functionality, efficiency, and effectiveness. I have also highlighted the individual perspectives on sustainable coastal development for the local case in northern Norway of Andøy Municipality and showed how shared perspectives that emerge from the local community can serve as a starting point for multi-sectoral cooperation and discussion. Finally, I conclude that to assure that the SDG localization process enables social transformations for sustainability, individual capacity must be activated and encouraged through participatory processes and stakeholder engagement that empowers social agency in ways that are self-sustaining and transcend scales. The SDGs, and sustainable development policies, are complex. They must stimulate transformative change across political, practical, and personal spheres by being rooted in universal values. I put forward an SDG localization process founded on principles of scientific quality and credibility, government legitimacy, and reflective of local and national needs. This unique approach provides a responsible, innovative, and trusted way forward for the integration of the global goals for sustainability into local society.Doktorgradsavhandlin

The effects of different versions of a gateway STEM course on student attitudes and beliefs

Background Substantial research has been conducted focusing on student outcomes in mathematics courses in order to better understand the ways in which these outcomes depend on the underlying instructional methodologies found in the courses. From 2009 to 2014, the Mathematical Association of America (MAA) studied Calculus I instruction in United States (US) colleges and universities in the Characteristics of Successful Programs of College Calculus (CSPCC). One aspect of this study attempted to understand the impact of these courses on student experience. Results In this paper, we describe results from an examination of the effect of course structure on students’ attitudes and beliefs across different versions of Calculus I at a large research university in the USA. To do this, we implemented a follow-up study of the national MAA study of calculus programs in part to identify potential relationships between various course structures and changes in attitudes and beliefs during the course. We compare our results both internally across these course structures and to the national data set. Conclusions We find that the statistically significant changes measured in confidence and enjoyment exhibit differences across the different calculus implementations and that these changes are statistically independent of the underlying student academic backgrounds as shown by standardized test scores and high school GPA. This suggests that these observed changes in attitudes and beliefs relate to the experience in our varied course structures and not to the academic characteristics of students as they enter the course. In addition to our findings, we show how this national study can be used locally to study effects of courses on student affective traits

Estamos en este pais: Motivations for English Language Acquisition among Adult Latino ESOL Students

Thesis advisor: Sarah BeckjordThis thesis examines the motivations for English language acquisition among Latino immigrants currently residing in the United States. By interviewing 34 adult students enrolled in ESOL classes in the Boston area, the author attempts to determine whether their desire for language acquisition is motivated by integrative or instrumental factors. These results are analyzed in light of the current debate on the assimilation of Latino immigrants, ultimately concluding that this segment of the population is indeed desirous of integration into the mainstream U.S. society.Thesis (BA) — Boston College, 2008.Submitted to: Boston College. College of Arts and Sciences.Discipline: Romance Languages and Literature.Discipline: College Honors Program

Driving Tour Narrative and Map of Historic Talbotton, Georgia

Talbot County Chamber of Commerce approached the Columbus Community Geography Center in December 2012 seeking help to update their historic driving tour of the county seat, Talbotton, GA. Students and faculty met several times with our community partner in Spring 2013. Students proposed preparing a new historic driving tour narrative and a tri-fold handout that would include a map locating each historic building featured on the tour

Investigating best practice : doctoral fieldwork experiences with and without Indigenous communities in settler-colonial societies

Through the sharing of personal commentaries about our doctoral fieldwork experiences, this paper contributes to decolonial literatures about academic knowledge generation in settler-colonial societies. The commentaries each illustrate shifting understandings of our roles in perpetuating the colonial knowledge-violence and material power of the academy, and our personal ethics to do something useful in response. Such experiences are often unreported or under reported for diverse reasons. Seeking to address injustice, and to move away from extractive research relationships, we highlight four matters: consent and risk; the resource gap in research collaborations; the consequences of not collaborating with Indigenous people; and, the importance of examining knowledge frames. As constrained and compromised as it is, we argue the doctoral experience is an important opportunity for decolonising the academy. Whilst we appreciate that this paper does not address the material circumstances that perpetuate colonial privilege, we go beyond descriptive reflection to offer prescriptions for change

Referral and triage patterns of a new rural paediatric outpatient service in south-western Victoria, Australia

Introduction: There is limited available information describing referral and triage patterns for rural paediatric outpatient clinics to guide health service planning and delivery. To address this, referrals for all new patients who attended an appointment during the initial year of a new rural paediatric outpatient service in Portland, Victoria, Australia were examined. Methods: This was a retrospective review of referrals with initial consultations between 29 October 2018 and 28 October 2019. Results: A total of 149 referrals for new patients were received, equating to a referral rate of 31.6 referrals per 1000 children for the service&#039;s Local Government Area (LGA). A total of 65.1% of new patients had not previously engaged with a paediatric service. Overall, 66.6% of referrals were triaged as having a behavioural or developmental problem. The median time from referral letter to initial appointment was 63 days, with referrals that were triaged as behavioural or developmental having an average wait time of 86 days until initial appointment. Conclusion: The establishment of this new rural paediatric service showed a latent need within the service&#039;s LGA, as demonstrated by higher referral rates compared to previously published studies and a majority patient population who had not previously accessed paediatric services. The greatest area of need identified by referral analysis was for behavioural and developmental problems

Tracking integrated ecosystem assessments in the ICES network: a social network analysis of the ICES expert groups

The advice the International Council for the Exploration of the Sea (ICES) provides to its member countries is crucial for the sustainable management of shared marine resources, and the conservation of relevant marine ecosystems. In 2014, ICES made a strategic decision to integrate marine and social sciences in a new type of assessment framework called “integrated ecosystem assessments” (IEA) to deliver advice on societal trade-offs between different policy options. The IEA-focused expert groups formed before and after this period now cover all major ecoregions. To track the progression of IEAs in the ICES network over time, we conducted a social network analysis (SNA) on expert group attendance for the years 2015–2019. The IEA-focused expert groups generally ranked lower in the overall ICES network. Our study shows that some IEA-groups become more connected over time, while others decline. We also evaluated the role of workshops in the ICES network, particularly their role in the development of IEA knowledge. Our study shows that workshops play an important role in ICES network connectivity. The study demonstrates how social network analysis can be used to study an organization such as ICES and determine the effectiveness, or impact, of that organizational function.publishedVersio