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 × 10(-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.     

Fixed or Probable Ideas?

This commentary on Nescolarde-Selva and Usó-Doménech (Found Sci, 2013) raises questions about the dynamic versus static nature of the model proposed, and in addition asks whether the model might be used to explain ethical flexibility and rigidity.     

Systems and Beliefs

Systems thinking provides insights into how ideas interact and change, and constructivism is an example of this type of systemic approach. In the 1970s constructivism emphasised the development of mathematical and scientific ideas in children. Recently constructivist ideas are applied much more generally. Here I use this approach to consider beliefs and their role in conflicts and the conditions needed for reconciliation. If we look at Reality in terms of how we construct it as a human cognitive process, we recognise two things. First, that we cannot go beyond our senses and thoughts to what exists independently of us, and second, if we construct what we know we have to take responsibility for this. This inevitably focuses our thinking on the relation we have with the physical and social world, we are a part of the universe rather than apart from it. This paper argues that accepting and understanding these limits of human knowing together with our interconnectedness provide opportunities to understand conflicting positions. To resolve conflict, people with opposing viewpoints have to be prepared to understand each other. That is a challenge because our own reality plays a vital role in our lives, for everything from personal survival to social support.     

Science,Respect for Nature,and Human Well-Being: Democratic Values and the Responsibilities of Scientists Today

The central question addressed is: How should scientific research be conducted so as to ensure that nature is respected and the well being of everyone everywhere enhanced? After pointing to the importance of methodological pluralism for an acceptable answer and to obstacles posed by characterizing scientific methodology too narrowly, which are reinforced by the ‘commercial-scientific ethos’, two additional questions are considered: How might research, conducted in this way, have impact on—and depend on—strengthening democratic values and practices? And: What is thereby implied for the responsibilities of scientists today?     

Observations of reproduction in mountain lions from Nebraska

Occurrences of mountain lions ( Puma concolor ) in Nebraska have been steadily increasing; however, reproductive activity in mountain lions has not been documented in the state. We present the first evidence of mountain lion reproduction in Nebraska since mountain lions recolonized the state in the early 1990s. On 28 February 2007, a spotted kitten was hit by a vehicle in northwestern Nebraska; and based on body length and weight, we estimate its age at 3.9 months. On 20 December 2008, a female mountain lion and spotted kitten were photographed in the northwestern part of the state. On 9 May 2009, a female mountain lion with a juvenile was also photographed. All records were from the Pine Ridge region of Dawes County, Nebraska. Our records suggest that mountain lions are establishing a permanent population in at least one region of Nebraska.     

Light-dependent phosphorylation of Bardet–Biedl syndrome 5 in photoreceptor cells modulates its interaction with arrestin1

Arrestins are dynamic proteins that move between cell compartments triggered by stimulation of G-protein-coupled receptors. Even more dynamically in vertebrate photoreceptors, arrestin1 (Arr1) moves between the inner and outer segments according to the light conditions. Previous studies have shown that the light-driven translocation of Arr1 in rod photoreceptors is initiated by rhodopsin through a phospholipase C/protein kinase C (PKC) signaling cascade. The purpose of this study is to identify the PKC substrate that regulates the translocation of Arr1. Mass spectrometry was used to identify the primary phosphorylated proteins in extracts prepared from PKC-stimulated mouse eye cups, confirming the finding with in vitro phosphorylation assays. Our results show that Bardet–Biedl syndrome 5 (BBS5) is the principal protein phosphorylated either by phorbol ester stimulation or by light stimulation of PKC. Via immunoprecipitation of BBS5 in rod outer segments, Arr1 was pulled down; phosphorylation of BBS5 reduced this co-precipitation of Arr1. Immunofluorescence and immunoelectron microscopy showed that BBS5 principally localizes along the axonemes of rods and cones, but also in photoreceptor inner segments, and synaptic regions. Our principal findings in this study are threefold. First, we demonstrate that BBS5 is post-translationally regulated by phosphorylation via PKC, an event that is triggered by light in photoreceptor cells. Second, we find a direct interaction between BBS5 and Arr1, an interaction that is modulated by phosphorylation of BBS5. Finally, we show that BBS5 is distributed along the photoreceptor axoneme, co-localizing with Arr1 in the dark. These findings suggest a role for BBS5 in regulating light-dependent translocation of Arr1 and a model describing its role in Arr1 translocation is proposed.     

Albedo of the south pole on Mars determined by topographic forcing of atmosphere dynamics

The nature of the martian south polar cap has remained enigmatic since the first spacecraft observations. In particular, the presence of a perennial carbon dioxide ice cap, the formation of a vast area of black 'slab ice' known as the Cryptic region and the asymmetric springtime retreat of the cap have eluded explanation. Here we present observations and climate modelling that indicate the south pole of Mars is characterized by two distinct regional climates that are the result of dynamical forcing by the largest southern impact basins, Argyre and Hellas. The style of surface frost deposition is controlled by these regional climates. In the cold and stormy conditions that exist poleward of 60 degrees S and extend 180 degrees in longitude west from the Mountains of Mitchel (approximately 30 degrees W), surface frost accumulation is dominated by precipitation. In the opposite hemisphere, the polar atmosphere is relatively warm and clear and frost accumulation is dominated by direct vapour deposition. It is the differences in these deposition styles that determine the cap albedo.