GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification

Conventional measurements of fasting and postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA variability on ‘around the clock’ glucoregulatory processes. Here we show that GWAS meta-analysis of glucose measurements under nonstandardized conditions (random glucose (RG)) in 476,326 individuals of diverse ancestries and without diabetes enables locus discovery and innovative pathophysiological observations. We discovered 120 RG loci represented by 150 distinct signals, including 13 with sex-dimorphic effects, two cross-ancestry and seven rare frequency signals. Of these, 44 loci are new for glycemic traits. Regulatory, glycosylation and metagenomic annotations highlight ileum and colon tissues, indicating an underappreciated role of the gastrointestinal tract in controlling blood glucose. Functional follow-up and molecular dynamics simulations of lower frequency coding variants in glucagon-like peptide-1 receptor (GLP1R), a type 2 diabetes treatment target, reveal that optimal selection of GLP-1R agonist therapy will benefit from tailored genetic stratification. We also provide evidence from Mendelian randomization that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Our investigation yields new insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification.</p

Partitioning uncertainty in projections of Arctic sea ice

Improved knowledge of the contributing sources of uncertainty in projections of Arctic sea ice over the 21st century is essential for evaluating impacts of a changing Arctic environment. Here, we consider the role of internal variability, model structure and emissions scenario in projections of Arctic sea-ice area (SIA) by using six single model initial-condition large ensembles and a suite of models participating in Phase 5 of the Coupled Model Intercomparison Project. For projections of September Arctic SIA change, internal variability accounts for as much as 40%–60% of the total uncertainty in the next decade, while emissions scenario dominates uncertainty toward the end of the century. Model structure accounts for 60%–70% of the total uncertainty by mid-century and declines to 30% at the end of the 21st century in the summer months. For projections of wintertime Arctic SIA change, internal variability contributes as much as 50%–60% of the total uncertainty in the next decade and impacts total uncertainty at longer lead times when compared to the summertime. In winter, there exists a considerable scenario dependence of model uncertainty with relatively larger model uncertainty under strong forcing compared to weak forcing. At regional scales, the contribution of internal variability can vary widely and strongly depends on the calendar month and region. For wintertime SIA change in the Greenland-Iceland-Norwegian and Barents Seas, internal variability contributes 60%–70% to the total uncertainty over the coming decades and remains important much longer than in other regions. We further find that the relative contribution of internal variability to total uncertainty is state-dependent and increases as sea ice volume declines. These results demonstrate that internal variability is a significant source of uncertainty in projections of Arctic sea ice

Indigenous entrepreneurship: Closing the gap on local terms

Within the federal government ‘Closing the Gap’ policy context this paper reports on local entrepreneurial activities by local Yolngu people in East Arnhem Land in the Northern Territory. Particular attention is directed to members of the Rirratjingu clan in the town of Yirrkala. We describe how the activities of a local social enterprise offer pathways for the creation of income, employment and social capital within the local community and where the protection of cultural vitality and integrity is axiomatic. The findings point to the need for more flexible policy approaches, to enable the establishment and growth of Indigenous business activities outside the economic mainstream. We echo the calls in the literature for policy support for what has been described as the ‘hybrid economy’, which allows for participation in both economic and cultural activities

Australian indigenous social enterprise: Measuring performance

Purpose Using an integrated framework for performance management of nonprofit organisations, this paper presents an analysis of the activities of an Indigenous social enterprise in the town of Yirrkala in northeast Arnhem Land in the Northern Territory of Australia. The evaluation focuses on the social effectiveness of the organisation and its ability to help generate income and employment and drive social capital creation. Design/methodology/approach The analysis is informed by data derived from ‘yarns’ with social enterprise staff and semi-structured interviews conducted with key informants who were selected using snowball sampling. Data were transcribed and analysed thematically. Findings The analysis reveals that the organisation provides a successful community-based pathway to increasing Indigenous economic participation on local terms at a time of regional economic decline and high levels of Indigenous unemployment nationally. Practical implications The measured effectiveness of Nuwul highlights the need for targeted policy support for Indigenous enterprises and that social entrepreneurship is far more likely to be successful in a supportive government policy environment. a critical need for government-initiated policies to encourage the formation of Indigenous social enterprises that are entrepreneurial and innovative in their solutions to poverty and marginalization. Such policies should not only aid the establishment of Indigenous ventures but also facilitate their long-term growth and sustainability. Originality/value While Indigenous entrepreneurial activities have been found to be effective in addressing Indigenous disadvantage in Australia, little is known about their community impact. The article provides original empirically grounded research on the measurement of Indigenous entrepreneurial activities and their wider community impact. The data show, against the backdrop of mixed results of government efforts to drive Indigenous economic mainstreaming, that the entrepreneurial activities analyzed in this paper are an example of more flexible and culturally appropriate pathways to achieving Indigenous equality in rural and remote regions of Australia

Partitioning uncertainty in projections of Arctic sea ice

Improved knowledge of the contributing sources of uncertainty in projections of Arctic sea ice over the 21st century is essential for evaluating impacts of a changing Arctic ecosystem. Here, we consider the role of internal variability, model structure and emissions scenario in projections of Arctic sea-ice extent (SIE) by using six single model initial-condition large ensembles and a suite of models participating in Phase 5 of the Coupled Model Intercomparison Project. For projections of September Arctic SIE, internal variability accounts for as much as 60% of the total uncertainty in the next few decades, while emissions scenario dominates uncertainty toward the end of the century. Model structure accounts for approximately 70% of the total uncertainty by mid-century and declines to 20% at the end of the 21st century. For projections of wintertime Arctic SIE, internal variability contributes as much as 60% of the total uncertainty in the first few decades and impacts total uncertainty at longer lead times when compared to summer SIE. Model structure contributes the rest of the uncertainty with emissions scenario contributing little to the total uncertainty. At regional scales, the contribution of internal variability can vary widely and strongly depends on the month and region. For wintertime SIE in the GIN and Barents Seas, internal variability contributes approximately 70% to the total uncertainty over the coming decades and remains important much longer than in other regions. We further find that the relative contribution of internal variability to total uncertainty is state-dependent and increases as sea ice volume declines. These results demonstrate the need to improve the representation of internal variability of Arctic SIE in models, which is a significant source of uncertainty in future projections

Indigenous entrepreneurship: Closing the gap on local terms

Australian federal government policy over the last ten years has renewed the focus on closing the gap between Indigenous and non-Indigenous Australians, targeting chiefly improvements in health and economic participation among Indigenous people. Thus far, however, the results have been mixed, in part because of the endurance of Indigenous socio-economic disadvantage in Australia which cannot be expected to be undone within a matter of years. Failure to deliver better policy outcomes, however, can also be seen as a function of an inflexible policy design, which aims at the mainstreaming of Indigenous communities on non-Indigenous terms, whilst militating against the potential for Indigenous entrepreneurial activities especially in rural and remote regions.Against this policy background, this paper reports on local entrepreneurial activities by local Yolngu clans in East Arnhem Land in the Northern Territories (NT). In particular, attention is directed to local for-profit and not-for-profit activities by members of the Gumatj clan south of the regional centre of Nhulunbuy and the Rirratjingu operations in the town Yirrkala respectively. The paper describes how the ventures run by the Gumatj and Rirratjingu clans offer pathways for the creation of income, employment and social capital within the respective local communities whilst also being axiomatic in the protection of cultural vitality and integrity. The findings point to the need for more flexible approaches to policy design and delivery, enabling the establishment and growth of Indigenous business activities outside the economic mainstream targeted by federal government policy. As such, the authors echo calls in the literature for policy support for what has been described as the 'hybrid economy', which allows for participation in both economic and cultural activities both of which are crucial for Indigenous future well-being as they are for any cultural group

Neonatal Vitamin D Levels in Relation to Risk of Overweight at 7 Years in the Danish D-Tect Case-Cohort Study

Background: Vitamin D level in pregnancy may be associated with risk of overweight in the offspring later in life. Methods: In a case-cohort study based on Danish biobanks and registers we examined the association between 25-hydroxy-vitamin D (25(OH)D) level at birth and overweight at 7 years. Cases of overweight (n = 871) were randomly selected among 7-year-old children from the Copenhagen School Health Records Register (CSHRR) with a BMI above the 90th percentile. The cohort (n = 1,311) was a random sample selected among all Danish children born during the same period. Neonatal 25(OH)D was measured in dried blood spots. Results: 25(OH)D3 exhibited the expected seasonal variation. Median level of 25(OH)D3 was 20.6 (11.9-33.3) nmol/l in the overweight group and 23.4 (13.5-34.3) nmol/l in the cohort. We found no association between neonatal 25(OH)D3 level and risk of overweight at age 7 years, neither in the crude model (OR (CI) 1.00 (0.99; 1.00)) nor in a model adjusted for maternal ethnicity, educational level, civil status, parity, season and year of birth, and offspring ponderal index (OR (CI) 1.00 (0.99; 1.01)). Conclusion: Risk of overweight at 7 years of age was not associated with vitamin D level at birth

Properties of branes in curved spacetimes

A generic property of curved manifolds is the existence of focal points. We show that branes located at focal points of the geometry satisfy special properties. Examples of backgrounds to which our discussion applies are AdS_m x S^n and plane wave backgrounds. As an example, we show that a pair of AdS_2 branes located at the north and south pole of the S^5 in AdS_5 x S^5 are half supersymmetric and that they are dual to a two-monopole solution of N=4 SU(N) SYM theory. Our second example involves spacelike branes in the (Lorentzian) plane wave. We develop a modified lightcone gauge for the open string channel, analyze in detail the cylinder diagram and establish open-closed duality. When the branes are located at focal points of the geometry the amplitude acquires most of the characteristics of flat space amplitudes. In the open string channel the special properties are due to stringy modes that become massless.Comment: 41 pages; v2:typos corrected, ref adde

Affective instability and impulsivity in borderline personality disorder

The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file.Title from title screen of research.pdf file (viewed on August 28, 2007)Includes bibliographical references.Thesis (M.A.) University of Missouri-Columbia 2006.Dissertations, Academic -- University of Missouri--Columbia -- Psychology.Affective instability and impulsivity are primary features of borderline personality disorder (BPD). We examined the effect of an interaction between these features, represented by FFM analogues of negative affectivity and disinhibition, on the expression of BPD symptoms. Our sample consisted of college undergraduates, a portion of whom endorsed clinically significant borderline personality features, assessed twice over two years. Results indicate that the interaction between affective instability and impulsivity accounted for a significant amount of variance in BPD symptoms, measured both concurrently and prospectively. These findings suggest that individuals high in both negative affectivity and disinhibition exhibited increased levels of BPD symptomatology, even after controlling for comorbid mood and substance use disorders. These results are important for understanding the etiology and course of BPD and for improving assessment, diagnosis, and treatment of BPD

Overoxidation of 2-cys peroxiredoxin in prokaryotes: Cyanobacterial 2-cys peroxiredoxins sensitive to oxidative stress

In eukaryotic organisms, hydrogen peroxide has a dual effect; it is potentially toxic for the cell but also has an important signaling activity. According to the previously proposed floodgate hypothesis, the signaling activity of hydrogen peroxide in eukaryotes requires a transient increase in its concentration, which is due to the inactivation by overoxidation of 2-Cys peroxiredoxin (2-Cys Prx). Sensitivity to overoxidation depends on the structural GGLG and YF motifs present in eukaryotic 2-Cys Prxs and is believed to be absent from prokaryotic enzymes, thus representing a paradoxical gain of function exclusive to eukaryotic organisms. Here we show that 2-Cys Prxs from several prokaryotic organisms, including cyanobacteria, contain the GG(L/ V/I)G and YF motifs characteristic of sensitive enzymes. In search of the existence of overoxidation-sensitive 2-Cys Prxs in prokaryotes, we have analyzed the sensitivity to overoxidation of 2-Cys Prxs from two cyanobacterial strains, Anabaena sp. PCC7120 and Synechocystis sp. PCC6803. In vitro analysis of wild type and mutant variants of the Anabaena 2-Cys Prx showed that this enzyme is overoxidized at the peroxidatic cysteine residue, thus constituting an exception among prokaryotes. Moreover, the 2-Cys Prx from Anabaena is readily and reversibly overoxidized in vivo in response to high light and hydrogen peroxide, showing higher sensitivity to overoxidation than the Synechocystis enzyme. These cyanobacterial strains have different strategies to cope with hydrogen peroxide. While Synechocystis has low content of less sensitive 2-Cys Prx and high catalase activity, Anabaena contains abundant and sensitive 2-Cys Prx, but low catalase activity, which is remarkably similar to the chloroplast system.Ministerio de Educación y Ciencia BIO2007-60644, BFU2007-60300Junta de Andalucía P06-CVI01578, BIO-182, BIO-28