Variation in FTO contributes to childhood obesity and severe adult obesity

We identified a set of SNPs in the first intron of the FTO (fat mass and obesity associated) gene on chromosome 16q12.2 that is consistently strongly associated with early-onset and severe obesity in both adults and children of European ancestry with an experiment-wise P value of 1.67 x 10(-26) in 2,900 affected individuals and 5,100 controls. The at-risk haplotype yields a proportion of attributable risk of 22% for common obesity. We conclude that FTO contributes to human obesity and hence may be a target for subsequent functional analyses.     

Estrogen receptor alpha (ESR1) gene amplification is frequent in breast cancer

Using an Affymetrix 10K SNP array to screen for gene copy number changes in breast cancer, we detected a single-gene amplification of the ESR1 gene, which encodes estrogen receptor alpha, at 6q25. A subsequent tissue microarray analysis of more than 2,000 clinical breast cancer samples showed ESR1 amplification in 20.6% of breast cancers. Ninety-nine percent of tumors with ESR1 amplification showed estrogen receptor protein overexpression, compared with 66.6% cancers without ESR1 amplification (P < 0.0001). In 175 women who had received adjuvant tamoxifen monotherapy, survival was significantly longer for women with cancer with ESR1 amplification than for women with estrogen receptor-expressing cancers without ESR1 amplification (P = 0.023). Notably, we also found ESR1 amplification in benign and precancerous breast diseases, suggesting that ESR1 amplification may be a common mechanism in proliferative breast disease and a very early genetic alteration in a large subset of breast cancers.     

Mathematical Models and Reality: A Constructivist Perspective

To explore the relation between mathematical models and reality, four different domains of reality are distinguished: observer-independent reality (to which there is no direct access), personal reality, social reality and mathematical/formal reality. The concepts of personal and social reality are strongly inspired by constructivist ideas. Mathematical reality is social as well, but constructed as an autonomous system in order to make absolute agreement possible. The essential problem of mathematical modelling is that within mathematics there is agreement about ‘truth’, but the assignment of mathematics to informal reality is not itself formally analysable, and it is dependent on social and personal construction processes. On these levels, absolute agreement cannot be expected. Starting from this point of view, repercussion of mathematical on social and personal reality, the historical development of mathematical modelling, and the role, use and interpretation of mathematical models in scientific practice are discussed.     

Intracellular NAD(H) levels control motility and invasion of glioma cells

Oncogenic transformation involves reprogramming of cell metabolism, whereby steady-state levels of intracellular NAD⁺ and NADH can undergo dramatic changes while ATP concentration is generally well maintained. Altered expression of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of NAD⁺-salvage, accompanies the changes in NAD(H) during tumorigenesis. Here, we show by genetic and pharmacological inhibition of NAMPT in glioma cells that fluctuation in intracellular [NAD(H)] differentially affects cell growth and morphodynamics, with motility/invasion capacity showing the highest sensitivity to [NAD(H)] decrease. Extracellular supplementation of NAD⁺ or re-expression of NAMPT abolished the effects. The effects of NAD(H) decrease on cell motility appeared parallel coupled with diminished pyruvate-lactate conversion by lactate dehydrogenase (LDH) and with changes in intracellular and extracellular pH. The addition of lactic acid rescued and knockdown of LDH-A replicated the effects of [NAD(H)] on motility. Combined, our observations demonstrate that [NAD(H)] is an important metabolic component of cancer cell motility. Nutrient or drug-mediated modulation of NAD(H) levels may therefore represent a new option for blocking the invasive behavior of tumors.     

Memory processes during sleep: beyond the standard consolidation theory

Two-step theories of memory formation suggest that an initial encoding stage, during which transient neural assemblies are formed in the hippocampus, is followed by a second step called consolidation, which involves re-processing of activity patterns and is associated with an increasing involvement of the neocortex. Several studies in human subjects as well as in animals suggest that memory consolidation occurs predominantly during sleep (standard consolidation model). Alternatively, it has been suggested that consolidation may occur during waking state as well and that the role of sleep is rather to restore encoding capabilities of synaptic connections (synaptic downscaling theory). Here, we review the experimental evidence favoring and challenging these two views and suggest an integrative model of memory consolidation.     

Skewed superstatistical distributions from a Langevin and Fokker-Planck approach

The superstatistics concept is a useful statistical method to describe inhomogeneous complex systems for which a system parameter βfluctuatesonalargespatio-temporal scale. Inthispaper weanalyze ameasuredtimeseriesofwindspeed fluctuationsandextract the superstatistical distribution function f(β) directly from the data. We construct suitable Langevin and Fokker-Planck models with a position dependent β-field and show that they reduce to standard type of superstatistics in the overdamped limit.