Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes

Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study. In a combined meta-analysis, we identified a SNP, rs11212617, associated with treatment success (n = 3,920, P = 2.9 P×-9, odds ratio = 1.35, 95% CI 1.22-1.49) at a locus containing ATM, the ataxia telangiectasia mutated gene. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMP-activated protein kinase in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to metformin. © 2011 Nature America, Inc. All rights reserved.

Hierarchically structured porous poly(2-oxazoline) hydrogels

A new method for fabricating hydrogels with intricate control over hierarchical 3D porosity using micro-fiber porogens is presented. Melt electrospinning writing of poly(ε-caprolactone) is used to create the sacrificial template leading to hierarchical structuring consisting of pores inside the denser poly(2-oxazoline) hydrogel mesh. This versatile approach provides new opportunities to create well-defined multilevel control over interconnected pores with diameters in the lower micrometer range inside hydrogels with potential applications as cell scaffolds with tunable diffusion and transport of, e.g. nutrients, growth factors or therapeutics.

Identification of a novel fusion transcript between human relaxin-1 (RLN1) and human relaxin-2 (RLN2) in prostate cancer

Simultaneous expression of highly homologous RLN1 and RLN2 genes in prostate impairs their accurate delineation. We used PacBio SMRT sequencing and RNA-Seq in LNCaP cells in order to dissect the expression of RLN1 and RLN2 variants. We identified a novel fusion transcript comprising the RLN1 and RLN2 genes and found evidence of its expression in the normal and prostate cancer tissues. The RLN1-RLN2 fusion putatively encodes RLN2 isoform with the deleted secretory signal peptide. The identification of the fusion transcript provided information to determine unique RLN1-RLN2 fusion and RLN1 regions. The RLN1-RLN2 fusion was co-expressed with RLN1 in LNCaP cells, but the two gene products were inversely regulated by androgens. We showed that RLN1 is underrepresented in common PCa cell lines in comparison to normal and PCa tissue. The current study brings a highly relevant update to the relaxin field, and will encourage further studies of RLN1 and RLN2 in PCa and broader.

Moving on (part 2): Power and the child in curriculum history

This paper is the second in a two-part series that maps continuities and ruptures in conceptions of power and traces their effects in educational discourse on 'the child'. It delineates two post-Newtonian intellectual trajectories through which concepts of 'power' arrived at the theorization of 'the child': the paradoxical bio-physical inscriptions of human-ness that accompanied mechanistic worldviews and the explanations for social motion in political philosophy. The intersection of pedagogical theories with 'the child' and 'power' is further traced from the latter 1800s to the present, where a Foucaultian analytics of power-as-effects is reconsidered in regard to histories of motion. The analysis culminates in an examination of post-Newtonian (dis)continuities in the theorization of power, suggesting some productive paradoxes that inhabit turn of the 21st-century conceptualizations of the social.

Self-assembly of indole-2-carboxylic acid at graphite and gold surfaces

Model systems are critical to our understanding of self-assembly processes. As such, we have studied the surface self-assembly of a small and simple molecule, indole-2-carboxylic acid (I2CA). We combine density functional theory gas-phase (DFT) calculations with scanning tunneling microscopy to reveal details of I2CA assembly in two different solvents at the solution/solid interface, and on Au(111) in ultrahigh vacuum (UHV). In UHV and at the trichlorobenzene/highly oriented pyrolytic graphite (HOPG) interface, I2CA forms epitaxial lamellar structures based on cyclic OH⋯O carboxylic dimers. The structure formed at the heptanoic acid/HOPG interface is different and can be interpreted in a model where heptanoic acid molecules co-adsorb on the substrate with the I2CA, forming a bicomponent commensurate unit cell. DFT calculations of dimer energetics elucidate the basic building blocks of these structures, whereas calculations of periodic two-dimensional assemblies reveal the epitaxial effects introduced by the different substrates.

The electronic properties of Si(001)–Bi(2 × n)

A Bi 2 × n surface net was grown on the Si(001) surface and studied with inverse photoemission, scanning tunnelling microscopy and ab initio and empirical pseudopotential calculations. The experiments demonstrated that Bi adsorption eliminates the dimer related π1* and π2* surface states, produced by correlated dimer buckling, leaving the bulk bandgap clear of unoccupied surface states. Ab initio calculations support this observation and demonstrate that the surface states derived from the formation of symmetric Bi dimers do not penetrate the fundamental bandgap of bulk Si. Since symmetric Bi dimers are an important structural component of the recently discovered Bi nanolines, that self-organize on Si(001) above the Bi desorption temperature, a connection will be made between our findings and the electronic structure of the nanolines.

Tie-2 regulates the stemness and metastatic properties of prostate cancer cells

Ample evidence supports that prostate tumor metastasis originates from a rare population of cancer cells, known as cancer stem cells (CSCs). Unfortunately, little is known about the identity of these cells, making it difficult to target the metastatic prostate tumor. Here, for the first time, we report the identification of a rare population of prostate cancer cells that express the Tie-2 protein. We found that this Tie-2High population exists mainly in prostate cancer cell lines that are capable of metastasizing to the bone. These cells not only express a higher level of CSC markers but also demonstrate enhanced resistance to the chemotherapeutic drug Cabazitaxel. In addition, knockdown of the expression of the Tie-2 ligand angiopoietin (Ang-1) led to suppression of CSC markers, suggesting that the Ang-1/Tie-2 signaling pathway functions as an autocrine loop for the maintenance of prostate CSCs. More importantly, we found that Tie-2High prostate cancer cells are more adhesive than the Tie-2Low population to both osteoblasts and endothelial cells. Moreover, only the Tie-2High, but not the Tie-2Low cells developed tumor metastasis in vivo when injected at a low number. Taken together, our data suggest that Tie-2 may play an important role during the development of prostate tumor metastasis.

On the construction of costs: McDermott v Robinson Helicopter Company (No.2) [2014] QSC 213

The decision in McDermott v Robinson Helicopter Company (No 2) [2014] QSC 213 involves an extensive examination of authorities on the general principle relating to the awarding of costs to a successful party. The court concluded that there was a predilection in favour of distributing costs according to the outcome or 'event' of particular issues in the action.

Direct electrochemical formation of nanostructured amorphous Co(OH)2 on gold electrodes with enhanced activity for the oxygen evolution reaction.

The oxides of cobalt have recently been shown to be highly effective electrocatalysts for the oxygen evolution reaction (OER) under alkaline conditions. In general species such as Co3O4 and CoOOH have been investigated that often require an elevated temperature step during their synthesis to create crystalline materials. In this work we investigate the rapid and direct electrochemical formation of amorphous nanostructured Co(OH)2 on gold electrodes under room temperture conditions which is a highly active precursor for the OER. During the OER some conversion to crystalline Co3O4 occurs at the surface, but the bulk of the material remains amorphous. It is found that the underlying gold electrode is crucial to the materials enhanced performance and provides higher current density than can be achieved using carbon, palladium or copper support electrodes. This catalyst exhibits excellent activity with a current density of 10 mA cm-2 at an overpotential of 360 mV with a high turnover frequency of 2.1 s-1 in 1 M NaOH. A Tafel slope of 56 mV dec-1 at low overpotentials and a slope of 122 mV dec-1 at high overpotentials is consistent with the dual barrier model for the electrocatalytic evolution of oxygen. Significantly, the catalyst maintains excellent activity for up to 24 hr of continuous operation and this approach offers a facile way to create a highly effective and stable material.

Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption

Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of approximately 2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based samples of European ancestry, comprising 26,316 individuals, with replication genotyping in an additional 21,185 individuals. SNP rs6943555 in autism susceptibility candidate 2 gene (AUTS2) was associated with alcohol consumption at genome-wide significance (P = 4 x 10(-8) to P = 4 x 10(-9)). We found a genotype-specific expression of AUTS2 in 96 human prefrontal cortex samples (P = 0.026) and significant (P < 0.017) differences in expression of AUTS2 in whole-brain extracts of mice selected for differences in voluntary alcohol consumption. Down-regulation of an AUTS2 homolog caused reduced alcohol sensitivity in Drosophila (P < 0.001). Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior.

Genome-wide association study identifies a locus at 7p15.2 associated with endometriosis

Endometriosis is a common gynecological disease associated with pelvic pain and subfertility. We conducted a genome-wide association study (GWAS) in 3,194 individuals with surgically confirmed endometriosis (cases) and 7,060 controls from Australia and the UK. Polygenic predictive modeling showed significantly increased genetic loading among 1,364 cases with moderate to severe endometriosis. The strongest association signal was on 7p15.2 (rs12700667) for 'all' endometriosis (P = 2.6 x 10(-)(7), odds ratio (OR) = 1.22, 95% CI 1.13-1.32) and for moderate to severe disease (P = 1.5 x 10(-)(9), OR = 1.38, 95% CI 1.24-1.53). We replicated rs12700667 in an independent cohort from the United States of 2,392 self-reported, surgically confirmed endometriosis cases and 2,271 controls (P = 1.2 x 10(-)(3), OR = 1.17, 95% CI 1.06-1.28), resulting in a genome-wide significant P value of 1.4 x 10(-)(9) (OR = 1.20, 95% CI 1.13-1.27) for 'all' endometriosis in our combined datasets of 5,586 cases and 9,331 controls. rs12700667 is located in an intergenic region upstream of the plausible candidate genes NFE2L3 and HOXA10.

Genome-wide linkage analysis of multiple measures of neuroticism of 2 large cohorts from Australia and the Netherlands

CONTEXT People meeting diagnostic criteria for anxiety or depressive disorders tend to score high on the personality scale of neuroticism. Studying this personality dimension can give insights into the etiology of these important psychiatric disorders. OBJECTIVES To undertake a comprehensive genome-wide linkage study of neuroticism using large study samples that have been measured multiple times and to compare the results between countries for replication and across time within countries for consistency. DESIGN Genome-wide linkage scan. SETTING Twin individuals and their family members from Australia and the Netherlands. PARTICIPANTS Nineteen thousand six hundred thirty-five sibling pairs completed self-report questionnaires for neuroticism up to 5 times over a period of up to 22 years. Five thousand sixty-nine sibling pairs were genotyped with microsatellite markers. METHODS Nonparametric linkage analyses were conducted in MERLIN-REGRESS for the mean neuroticism scores averaged across time. Additional analyses were conducted for the time-specific measures of neuroticism from each country to investigate consistency of linkage results. RESULTS Three chromosomal regions exceeded empirically derived thresholds for suggestive linkage using mean neuroticism scores: 10p 5 Kosambi cM (cM) (Dutch study sample), 14q 103 cM (Dutch study sample), and 18q 117 cM (combined Australian and Dutch study sample), but only 14q retained significance after correction for multiple testing. These regions all showed evidence for linkage in individual time-specific measures of neuroticism and 1 (18q) showed some evidence for replication between countries. Linkage intervals for these regions all overlap with regions identified in other studies of neuroticism or related traits and/or in studies of anxiety in mice. CONCLUSIONS Our results demonstrate the value of the availability of multiple measures over time and add to the optimism reported in recent reviews for replication of linkage regions for neuroticism. These regions are likely to harbor causal variants for neuroticism and its related psychiatric disorders and can inform prioritization of results from genome-wide association studies.

Changes in straylight and corneal light scattering in a newly diagnosed case of type 2 diabetes

Visual problems may be the first symptoms of diabetes. There have been several reports of transient changes in refraction of people newly diagnosed with diabetes. Visual acuity and refraction may be affected when there are ocular biometric changes. Small but significant biometrical changes have been found by some authors during hyperglycaemia and during reduction of hyperglycaemia.[4] Here, we describe a case of type 2 diabetes that was detected from ocular straylight and intraocular thickness measurements...

Editorial of "International Journal of Critical Indigenous Studies Volume 2, Number 1, 2009"

Over the past two decades neo liberalism has shaped global economic activity. The international reach of the current economic crisis propelled by the subprime mortgage meltdown in the United States has affected Indigenous communities in different ways to those whose investments were depleted by the Wall Street activities of an unregulated corporate and banking sector. Throughout this roller coaster economic ride the low socio-economic position of Indigenous peoples continued in Canada, the United States of America, New Zealand, Hawaii and Australia. The logic, or illogic of capital, failed to extend the boom of the economic upturn to Indigenous peoples, but is poised to extend the repercussions of the current downturn deep into Indigenous lives. The consistency of the Indigenous socio-economic position across these countries, even where treaties exist, indicates that the phenomenon is based on a shared Indigenous reality. In this special edition, the commonality in the way in which Indigenous people are engaged in and positioned by market forces and regulation by their respective nation states is proposed as one of the foundation plates of that Indigenous positioning...

Editorial of "International Journal of Critical Indigenous Studies Volume 2, Number 2, 2009"

This edition of the International Critical Indigenous Studies Journal, our second for 2009 takes alternative understandings as its theme. All four articles in this edition attend to citizenship and Indigenous sovereignty though in different ways...