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Aims: The aim of this study was to investigate the occurrence of myocardial injury and cardiac dysfunction after an endurance race by biomarkers and cardiac magnetic resonance in triathletes with and without myocardial fibrosis., Methods and Results: Thirty asymptomatic male triathletes (45 ± 10 years) with over 10 training hours per week and 55 ± 8 ml/kg per minute maximal oxygen uptake during exercise testing were studied before (baseline) and 2.4 ± 1.1 hours post-race. Baseline cardiac magnetic resonance included cine, T1/T2, late gadolinium enhancement (LGE) and extracellular volume imaging. Post-race non-contrast cardiac magnetic resonance included cine and T1/T2 mapping. Non-ischaemic myocardial fibrosis was present in 10 triathletes (LGE+) whereas 20 had no fibrosis (LGE-). At baseline, LGE + triathletes had higher peak exercise systolic blood pressure with 222 ± 21 mmHg compared to LGE- triathletes (192 ± 30 mmHg, P  < 0.01). Post-race troponin T and creatine kinase MB were similarly increased in both groups, but there was no change in T2 and T1 from baseline to post-race with 54 ± 3 ms versus 53 ± 3 ms ( P  = 0.797) and 989 ± 21 ms versus 989 ± 28 ms ( P  = 0.926), respectively. However, post-race left atrial ejection fraction was significantly lower in LGE + triathletes compared to LGE- triathletes (53 ± 6% vs. 59 ± 6%, P  < 0.05). Furthermore, baseline atrial peak filling rates were lower in LGE -  triathletes (121 ± 30 ml/s/m 2 ) compared to LGE + triathletes (161 ± 34 ml/s/m 2 , P  < 0.01). Post-race atrial peak filling rates increased in LGE- triathletes to 163 ± 46 ml/s/m 2 , P  < 0.001), but not in LGE + triathletes (169 ± 50ml/s/m 2 , P  = 0.747)., Conclusion: Despite post-race troponin T release, we did not find detectable myocardial oedema by cardiac magnetic resonance. However, the unfavourable blood pressure response during exercise testing seemed to be associated with post-race cardiac dysfunction, which could explain the occurrence of myocardial fibrosis in triathletes.

Transgenic mouse models are indispensable tools to mimic human diseases and analyze the effectiveness of related new drugs. For a long time amyotrophic lateral sclerosis (ALS) research depended on only a few mouse models that exhibit a very strong and early phenotype, e.g. SOD1 mice, resulting in a short treatment time window. By now, several models are available that need to be characterized to highlight characteristics of each model. Here we further characterized the mThy1-hTDP-43 transgenic mouse model TAR6/6 that overexpresses wild type human TARDBP, also called TDP-43, under control of the neuronal Thy-1 promoter presented by Wils and colleagues, 2010, by using biochemical, histological and behavioral readouts. Our results show that TAR6/6 mice exhibit a strong TDP-43 expression in the hippocampus, spinal cord, hypothalamus and medulla oblongata. Apart from prominent protein expression in the nucleus, TDP-43 protein was found at lower levels in the cytosol of transgenic mice. Additionally, we detected insoluble TDP-43 in the cortex, motoneuron loss, and increased neuroinflammation in the central nervous system of TAR6/6 animals. Behavioral analyses revealed early motor deficits in the clasping- and wire suspension test as well as decreased anxiety in the elevated plus maze. Further motor tests showed differences at later time points compared to non-transgenic littermates, thus allowing the observation of onset and severity of such deficits. Together, TAR6/6 mice are a valuable tool to test new ALS/FTLD drugs that target TDP-43 expression and insolubility, neuroinflammation, motoneuron loss or other TDP-43 related downstream signaling pathways since these mice exhibit a later pathology as previously used ALS/FTLD mouse models., Competing Interests: BS, RR, SF, JN, NT, MT, VN, BHP are employees of QPS Austria GmbH. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

α/β Hydrolase domain-containing 6 (ABHD6) can act as monoacylglycerol hydrolase and is believed to play a role in endocannabinoid signaling as well as in the pathogenesis of obesity and liver steatosis. However, the mechanistic link between gene function and disease is incompletely understood. Here we aimed to further characterize the role of ABHD6 in lipid metabolism. We show that mouse and human ABHD6 degrade bis(monoacylglycero)phosphate (BMP) with high specific activity. BMP, also known as lysobisphosphatidic acid, is enriched in late endosomes/lysosomes, where it plays a key role in the formation of intraluminal vesicles and in lipid sorting. Up to now, little has been known about the catabolism of this lipid. Our data demonstrate that ABHD6 is responsible for ∼ 90% of the BMP hydrolase activity detected in the liver and that knockdown of ABHD6 increases hepatic BMP levels. Tissue fractionation and live-cell imaging experiments revealed that ABHD6 co-localizes with late endosomes/lysosomes. The enzyme is active at cytosolic pH and lacks acid hydrolase activity, implying that it degrades BMP exported from acidic organelles or de novo-formed BMP. In conclusion, our data suggest that ABHD6 controls BMP catabolism and is therefore part of the late endosomal/lysosomal lipid-sorting machinery., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

To determine whether estrogen and androgens either alone or in combination downregulate estrogen receptors in the brain, ovariectomized/adrenalectomized female rats received one of the following four treatments: (1) one subcutaneously placed Silastic capsule containing 10% estradiol in cholesterol, (2) one capsule containing 10% estradiol and two capsules containing 100% 5 alpha-dihydrotestosterone (DHT), (3) two capsules containing DHT, or (4) empty Silastic capsules (control animals). Animals were killed 4 or 8 days after capsule insertion and the occupied, unoccupied and total estrogen receptor content in specific brain nuclei was determined by quantitative in vitro autoradiography. To determine if the effects of the androgen were reversible, DHT capsules were removed after 4 days from half of the estradiol+DHT-treated rats, and the animals were killed 4 days later. Estradiol downregulated estrogen receptor expression in the periventricular preoptic area, medial preoptic area, bed nucleus of the stria terminalis (BNST), arcuate nucleus (ARC), ventromedial nucleus (VMN), and medial and cortical amygdala, decreasing receptor content by 30-41% in animals treated for 4 days, and by 44-60% in animals treated for 8 days with estradiol alone. DHT treatment in combination with estradiol further decreased estrogen receptor content in the BNST, ARC and VMN, relative to the estradiol-only animals. DHT in the absence of estrogen was without effect. In animals in which the DHT capsules were removed after 4 days of exposure, allowing the estradiol to remain for a further 4 days, estrogen receptor levels were indistinguishable from those measured in control animals treated for 8 days with estradiol alone. These results demonstrate that sustained estrogen exposure downregulates levels of estrogen receptor in the brain and confirm that DHT synergizes with estrogen in inducing this response in some, but not all, target neuronal groups.

Multiple molecular forms contribute to various types of enzyme heterogeneity: "Iso(en)-zymes" and "Allozymes" (enzyme variants) are of genetic origin whereas "Metazymes" represent secondary modifications of epigenetic nature. The concept of variability originates from the discovery of a large number of enzyme variants. Structural gene mutations can lead to enzyme variants of low specific activity or reduced stability and can cause enzyme deficiencies. In heterozygous carriers of oligomeric enzyme defects, the formation of hybrid molecules is possible by random assembly of simultaneously synthetized normal and mutant subunits. The study of normal processes as well as enzyme anomalies contributes essentially to better understanding of biochemical individuality and evolutionary events at a molecular level.