Several genes with an essential role in the regulation of eating behavior and body weight are considered candidates involved in the etiology of eating disorders (ED), but no relevant susceptibility ...genes with a major effect on anorexia nervosa (AN) or bulimia nervosa (BN) have been identified. Brain-derived neurotrophic factor (BDNF) has been implicated in the regulation of food intake and body weight in rodents. We previously reported a strong association of the Met66 allele of the Val66Met BDNF variant with restricting AN (ANR) and low minimum body mass index in Spanish patients. Another single nucleotide polymorphism located in the promoter region of the BDNF gene (−270C>T) showed lack of association with any ED phenotype. In order to replicate these findings in a larger sample, we performed a case–control study in 1142 Caucasian patients with ED consecutively recruited in six different centers from five European countries (France, Germany, Italy, Spain and UK) participating in the ‘Factors in Healthy Eating’ project. We have found that the Met66 variant is strongly associated to all ED subtypes (AN, ANR, binge-eating/purging AN and BN), and that the −270C BDNF variant has an effect on BN and late age at onset of weight loss. These are the first two variants associated with the pathophysiology of ED in different populations and support a role for BDNF in the susceptibility to aberrant eating behaviors.
Eating disorders (ED), such as anorexia nervosa (AN) and bulimia nervosa (BN), are complex psychiatric disorders where different genetic and environmental factors are involved. Several lines of ...evidence support that brain-derived neurotrophic factor (BDNF) plays an essential role in eating behaviour and that alterations on this neurotrophic system participates in the susceptibility to both AN and BN. Accordingly, intraventricular administration of BDNF in rats determines food starvation and body weight loss, while BDNF or its specific receptor NTRK2 knockout mice develop obesity and hyperphagia. Case-control studies also suggest a BDNF contribution in the aetiology of ED: we have previously reported a strong association between the Met66 variant within the BDNF gene, restricting AN (ANR) and minimum body mass index (minBMI) in a Spanish sample, and a positive association between the Val66Met and -270C/T BDNF SNPs and ED in six different European populations. To replicate these results, avoiding population stratification effects, we recruited 453 ED trios from eight European centres and performed a family-based association study. Both haplotype relative risk (HRR) and haplotype-based haplotype relative risk (HHRR) methods showed a positive association between the Met66 allele and ANR. Consistently, we also observed an effect of the Met66 variant on low minBMI and a preferential transmission of the -270C/Met66 haplotype to the affected ANR offspring. These results support the involvement of BDNF in eating behaviour and further suggest its participation in the genetic susceptibility to ED, mainly ANR and low minBMI.
A-Kinase anchoring proteins (AKAPs) are a structurally diverse family of proteins defined by the ability to bind protein kinase A (PKA). AKAPs process and integrate a variety of intracellular signals ...by sequestering PKA with other signaling enzymes such as kinases, phosphodiesterases, and phosphatases. dAKAP1 tethers both PKA and protein phosphatase 1 (PP1) to the outer mitochondrial membrane and contains RNA and protein interaction domains that permit the clustering of signaling enzymes with the post-transcriptional machinery. The function of RNA binding by dAKAP1 at the outer mitochondrial membrane, however, is largely unresolved. I investigated two main questions: what are the protein and RNA binding partners of dAKAP1? and what is the physiological significance of the association of these molecules with dAKAP1? In order to answer the first question, I utilized mass spectrometry to identify protein interacting partners of dAKAP1 and discovered that dAKAP1 interacts with protein subcomplexes with RNA regulatory functions. I validated the interaction of one of these subcomplexes, LARP4/PABPC1, and determined that dAKAP1 binding of RNA is required for its localization to the outer mitochondrial membrane. I utilized RNA-Seq to identify RNA interacting partners of dAKAP1 and discovered that dAKAP1 can interact with RNAs that encode mitochondrial proteins. In order to answer the second question, I investigated the local translation of proteins encoded by RNA interacting partners of dAKAP1 at the mitochondria. I observed that dAKAP1-mediated anchoring of the SDHA mRNA directly correlates with mitochondrial SDHA protein levels. Though alternation of this anchoring is not sufficient to drive metabolic change, I also correlate a decrease of SDHA with a decrease in dAKAP1 levels across four different breast cancer cell lines. Collectively, my work suggests that dAKAP1 anchoring of both RNA and RNA-regulatory proteins is important for the local translation of at least one protein, SDHA, involved in the critical mitochondrial function of oxidative phosphorylation.
Steel with carbon content from 0.13 to 0.04% were rolled in the temperature range 1220 to 750 deg C and subsequently air cooled. The microstructure as well as mechanical properties were investigated. ...The grain size in steels is first gradually decreased with lowering rolling temperature, and then quickly increased with further lowering of rolling temperature to ferrite range. The microstructure is more coarse the heterogeneous the less completed the interpass recrystallisation of austenite and the more ferrite present in steel during the rolling. The rolling in ferrite range produces a strong anisotropy in tensile ductility. 7 ref.--AA
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