Heat shock-induced phosphorylation of TAR DNA-binding protein 43 (TDP-43) by MAPK/ERK kinase regulates TDP-43 function

TAR DNA-binding protein (TDP-43) is a highly conserved and essential DNA- and RNA-binding protein that controls gene expression through RNA processing, in particular, regulation of splicing. Intracellular aggregation of TDP-43 is a hallmark of amyotrophic lateral sclerosis and ubiquitin-positive frontotemporal lobar degeneration. This TDP-43 pathology is also present in other types of neurodegeneration including Alzheimer's disease. We report here that TDP-43 is a substrate of MEK, a central kinase in the MAPK/ERK signaling pathway. TDP-43 dual phosphorylation by MEK, at threonine 153 and tyrosine 155 (p-T153/Y155), was dramatically increased by the heat shock response (HSR) in human cells. HSR promotes cell survival under proteotoxic conditions by maintaining protein homeostasis and preventing protein misfolding. MEK is activated by HSR and contributes to the regulation of proteome stability. Phosphorylated TDP-43 was not associated with TDP-43 aggregation, and p-T153/Y155 remained soluble under conditions that promote protein misfolding. We found that active MEK significantly alters TDP-43-regulated splicing and that phosphomimetic substitutions at these two residues reduce binding to GU-rich RNA. Cellular imaging using a phospho-specific p-T153/Y155 antibody showed that phosphorylated TDP-43 was specifically recruited to the nucleoli, suggesting that p-T153/Y155 regulates a previously unappreciated function of TDP-43 in the processing of nucleolar-associated RNA. These findings highlight a new mechanism that regulates TDP-43 function and homeostasis through phosphorylation and, therefore, may contribute to the development of strategies to prevent TDP-43 aggregation and to uncover previously unexplored roles of TDP-43 in cell metabolism

Arginine and antioxidant supplement on performance in elderly male cyclists: a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Human exercise capacity declines with advancing age. These changes often result in loss of physical fitness and more rapid senescence. Nitric oxide (NO) has been implicated in improvement of exercise capacity through vascular smooth muscle relaxation in both coronary and skeletal muscle arteries, as well as via independent mechanisms. Antioxidants may prevent nitric oxide inactivation by oxygen free radicals. The purpose of this study was to investigate the effects of an L-arginine and antioxidant supplement on exercise performance in elderly male cyclists.</p> <p>Methods</p> <p>This was a two-arm prospectively randomized double-blinded and placebo-controlled trial. Sixteen male cyclists were randomized to receive either a proprietary supplement (Niteworks^®, Herbalife International Inc., Century City, CA) or a placebo powder. Exercise parameters were assessed by maximal incremental exercise testing performed on a stationary cycle ergometer using breath-by-breath analysis at baseline, week one and week three.</p> <p>Results</p> <p>There was no difference between baseline exercise parameters. In the supplemented group, anaerobic threshold increased by 16.7% (2.38 ± 0.18 L/min, p < 0.01) at week 1, and the effect was sustained by week 3 with a 14.2% (2.33 ± 0.44 L/min, p < 0.01). In the control group, there was no change in anaerobic threshold at weeks 1 and 3 compared to baseline (1.88 ± 0.20 L/min at week 1, and 1.86 ± 0.21 L/min at week 3). The anaerobic threshold for the supplement groups was significantly higher than that of placebo group at week 1 and week 3. There were no significant changes noted in VO₂max between control and intervention groups at either week 1 or week 3 by comparison to baseline.</p> <p>Conclusion</p> <p>An arginine and antioxidant-containing supplement increased the anaerobic threshold at both week one and week three in elderly cyclists. No effect on VO₂max was observed. This study indicated a potential role of L-arginine and antioxidant supplementation in improving exercise performance in elderly.</p

Mixed Spices at Culinary Doses Have Prebiotic Effects in Healthy Adults: A Pilot Study.

Spices were used as food preservatives prior to the advent of refrigeration, suggesting the possibility of effects on microbiota. Previous studies have shown prebiotic activities in animals and in vitro, but there has not been a demonstration of prebiotic or postbiotic effects at culinary doses in humans. In this randomized placebo-controlled study, we determined in twenty-nine healthy adults the effects on the gut microbiota of the consumption daily of capsules containing 5 g of mixed spices at culinary doses by comparison to a matched control group consuming a maltodextrin placebo capsule. The 16S ribosomal RNA sequencing data were used for microbial characterization. Spice consumption resulted in a significant reduction in Firmicutes abundance (p &lt; 0.033) and a trend of enrichment in Bacteroidetes (p &lt; 0.097) compared to placebo group. Twenty-six operational taxonomic units (OTUs) were different between the spice and placebo groups after intervention. Furthermore, there was a significant negative correlation between fecal short-chain fatty acid propionate concentration and Firmicutes abundance in spice intervention group (p &lt; 0.04). The production of individual fecal short-chain fatty acid was not significantly changed by spice consumption in this study. Mixed spices consumption significantly modified gut microbiota, suggesting a prebiotic effect of spice consumption at culinary doses

Application of finite element modeling and viscoelasticity theory in characterization and prediction of dielectric relaxation process in polymer nanodielectrics

Nanodielectrics, typically defined as polymer composites with nanosized ceramic fillers, have demonstrated significant improvements in electrical endurance, breakdown strength and dielectric constant relative to their constituent materials, which leads to enhanced energy storage capabilities. The key role played by the large interfacial area surrounding nanofillers proves to be essential to the enhancement, yet quantitative models to predict the altered dielectric properties in the interfacial area are rarely seen. In this presentation, we apply a finite element modeling approach, originally developed for viscoelasticity analysis, to predict the frequency and temperature dependence of dielectric permittivity spectra in polymer nanodielectrics containing functionalized silica fillers. The dispersion state of nanofillers in the finite element model is determined from descriptor-based analysis of scanning electron micrographs, and the interfacial area surrounding the fillers is explicitly configured into the geometry. The dielectric permittivity spectra of the polymer matrix are imported into the model using a series of Debye relaxation functions. The analogy between dielectric permittivity and viscoelastic modulus allows for a simple mathematical conversion between the two physically distinct quantities, which enables the usage of Prony Series when fitting the dielectric spectrum. With the assistance of a earlier developed algorithm to fit the viscoelastic modulus, the parameters of Debye relaxation series function are obtained. Using the above morphology and physical property inputs, dielectric spectroscopy experiments over a range of frequencies and temperatures can be simulated. Properties of the interfacial region are obtained through an iterative comparison between model output and experimental results. It is observed that the distribution of dielectric relaxation times of the interface could be expressed using those of the polymer matrix multiplied by frequency shift factors that vary with different functionalization of the silica filler surfaces. Our results indicate that surface energy parameters of the filler and the polymer matrix can vary the dielectric response of the composites, which is consistent with earlier observations of the viscoelastic properties of polymer nanocomposites. Further discussion on the results also provides insight into the underlying dielectric relaxation mechanism in the interfacial area

Adaptive Response Enzyme AlkB Preferentially Repairs 1-Methylguanine and 3-Methylthymine Adducts in Double-Stranded DNA

The AlkB protein is a repair enzyme that uses an α-ketoglutarate/Fe(II)-dependent mechanism to repair alkyl DNA adducts. AlkB has been reported to repair highly susceptible substrates, such as 1-methyladenine and 3-methylcytosine, more efficiently in ss-DNA than in ds-DNA. Here, we tested the repair of weaker AlkB substrates 1-methylguanine and 3-methylthymine and found that AlkB prefers to repair them in ds-DNA. We also discovered that AlkB and its human homologues, ABH2 and ABH3, are able to repair the aforementioned adducts when the adduct is present in a mismatched base pair. These observations demonstrate the strong adaptability of AlkB toward repairing various adducts in different environments. (Chemical Equation Presented)

What Makes Theatrical Performances Successful in China's Tourism Industry?

This study aims to explore the factors affecting the success of a popular tourist product, namely, theatrical performance, within the context of China's tourism industry and develop a model based on previously successful productions. Using qualitative software, 22 Chinese-language articles on theatrical performances are analyzed to generate a list of success factors, classified as internal and external. The internal factors are storyline and performing, market positioning and marketing strategy, investment and financial support, operation and management, performing team, outdoor venue, indoor/outdoor stage supporting facilities, continuous improvement, and production team. The external factors are collaboration between cultural industries and local tourism, government support, privatization, and social and cultural effect. This study also provides suggestions for the future development of theatrical performances in China