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Skeletal muscle tissue demonstrates global hypermethylation with age. However, methylome changes across the time-course of differentiation in aged human muscle derived cells, and larger coverage arrays in aged muscle tissue have not been undertaken. Using 850K DNA methylation arrays we compared the methylomes of young (27 ± 4.4 years) and aged (83 ± 4 years) human skeletal muscle and that of young/aged heterogenous muscle-derived human primary cells (HDMCs) over several time points of differentiation (0, 72 h, 7, 10 days). Aged muscle tissue was hypermethylated compared with young tissue, enriched for; pathways-in-cancer (including; focal adhesion, MAPK signaling, PI3K-Akt-mTOR signaling, p53 signaling, Jak-STAT signaling, TGF-beta and notch signaling), rap1-signaling, axon-guidance and hippo-signalling. Aged cells also demonstrated a hypermethylated profile in pathways; axon-guidance, adherens-junction and calcium-signaling, particularly at later timepoints of myotube formation, corresponding with reduced morphological differentiation and reductions in MyoD/Myogenin gene expression compared with young cells. While young cells showed little alterations in DNA methylation during differentiation, aged cells demonstrated extensive and significantly altered DNA methylation, particularly at 7 days of differentiation and most notably in focal adhesion and PI3K-AKT signalling pathways. While the methylomes were vastly different between muscle tissue and HDMCs, we identified a small number of CpG sites showing a hypermethylated state with age, in both muscle tissue and cells on genes KIF15 , DYRK2 , FHL2 , MRPS33 , ABCA17P . Most notably, differential methylation analysis of chromosomal regions identified three locations containing enrichment of 6–8 CpGs in the HOX family of genes altered with age. With HOXD10 , HOXD9 , HOXD8 , HOXA3 , HOXC9 , HOXB1 , HOXB3 , HOXC-AS2 and HOXC10 all hypermethylated in aged tissue. In aged cells the same HOX genes (and additionally HOXC-AS3 ) displayed the most variable methylation at 7 days of differentiation versus young cells, with HOXD8 , HOXC9 , HOXB1 and HOXC-AS3 hypermethylated and HOXC10 and HOXC-AS2 hypomethylated. We also determined that there was an inverse relationship between DNA methylation and gene expression for HOXB1 , HOXA3 and HOXC-AS3 . Finally, increased physical activity in young adults was associated with oppositely regulating HOXB1 and HOXA3 methylation compared with age. Overall, we demonstrate that a considerable number of HOX genes are differentially epigenetically regulated in aged human skeletal muscle and HDMCs and increased physical activity may help prevent age-related epigenetic changes in these HOX genes.

A large body of experimental data have shown that aerobic exercise of different duration, intensity, and pattern affect molecular mechanisms regulating mitochondrial biogenesis in skeletal muscles. This review focuses on the effects of exercise duration and intensity on the molecular mechanisms of mitochondrial biogenesis regulation in skeletal muscles, namely PGC-1α-dependent signaling. Studies of the effects of acute exercise and exercise training showed that an increase in the duration of aerobic exercise from 30 to 90 min does not provide additional stimuli to activate signaling pathways regulating post-translational modification of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and expression of the PGC-1α gene (PPARGC1A). Conversely, exercise intensity substantially affects mitochondrial biogenesis due to the increase in the recruitment of type II muscle fibers with accompanying pronounced metabolic shift leading to the activation of signaling cascades and expression of genes regulating mitochondrial biogenesis. Therefore, intermittent exercise, which recruits type II muscle fibers, is more efficient in the activation of mitochondrial biogenesis than work-matched continuous exercise. In skeletal muscle adapted to aerobic training, intensity-dependent activation of mitochondrial biogenesis after acute exercise is associated primarily with the AMP-activated protein kinase/PGC-1α pathway, expression of PGC-1α-regulated genes, and expression of PPARGC1A from the alternative (distal) inducible promoter regulated by the cAMP response element-binding protein 1-related transcription factors and their coactivators. Elucidation of the effects of duration and intensity of aerobic exercise on the PGC-1α-dependent and -independent mechanisms of mitochondrial biogenesis is important for treatment of patients with various metabolic disorders, as well as for optimization of training in athletes.

High-pressure electrical resistivity measurements reveal that the mechanical deformation of ultra-hard WB 2 during compression induces superconductivity above 50 GPa with a maximum superconducting critical temperature, T c of 17 K at 91 GPa. Upon further compression up to 187 GPa, the T c gradually decreases. Theoretical calculations show that electron-phonon mediated superconductivity originates from the formation of metastable stacking faults and twin boundaries that exhibit a local structure resembling MgB 2 (hP3, space group 191, prototype AlB 2 ). Synchrotron x-ray diffraction measurements up to 145 GPa show that the ambient pressure hP12 structure (space group 194, prototype WB 2 ) continues to persist to this pressure, consistent with the formation of the planar defects above 50 GPa. The abrupt appearance of superconductivity under pressure does not coincide with a structural transition but instead with the formation and percolation of mechanically-induced stacking faults and twin boundaries. The results identify an alternate route for designing superconducting materials. In 2001 superconductivity with a high critical temperature of 39 K was discovered in MgB 2 , but efforts since then to identify other diboride-family superconductors have been mostly unsuccessful. Here, the authors report the discovery of superconductivity in pressurized WB 2 , originating from the formation of metastable stacking faults and twin boundaries that exhibit a local structure resembling MgB 2 .

—A three-dimensional geoelectric model of the tectonosphere has been constructed, containing typical geoelectric heterogeneities at three structural levels: uplift and subsidence of the roof of the basement, conductive prisms in the consolidated crust, and asthenospheric uplift in the upper mantle. Synthetic magnetotelluric data were calculated, and their sensitivity to geoelectric structures was analyzed. A two-dimensional smoothing inversion of synthetic data was performed along two perpendicular profiles. Despite significant three-dimensional effects, the obtained sections quite accurately reconstruct the position of the roof of the basement, obtain rough images of crustal structures, and poorly resolve the structure of the mantle. The influence of random noise of different levels on the inversion results is assessed. In the future, it is planned to perform three-dimensional inversion of synthetic data.

The presence of diffuse anaplasia in Wilms tumours (DAWT) is associated with TP53 mutations and poor outcome. As patients receive intensified treatment, we sought to identify whether TP53 mutational status confers additional prognostic information. We studied 40 patients with DAWT with anaplasia in the tissue from which DNA was extracted and analysed for TP53 mutations and 17p loss. The majority of cases were profiled by copy number (n = 32) and gene expression (n = 36) arrays. TP53 mutational status was correlated with patient event-free and overall survival, genomic copy number instability and gene expression profiling. From the 40 cases, 22 (55%) had TP53 mutations (2 detected only after deep-sequencing), 20 of which also had 17p loss (91%); 18 (45%) cases had no detectable mutation but three had 17p loss. Tumours with TP53 mutations and/or 17p loss (n = 25) had an increased risk of recurrence as a first event (p = 0.03, hazard ratio (HR), 3.89; 95% confidence interval (CI), 1.26-16.0) and death (p = 0.04, HR, 4.95; 95% CI, 1.36-31.7) compared to tumours lacking TP53 abnormalities. DAWT carrying TP53 mutations showed increased copy number alterations compared to those with wild-type, suggesting a more unstable genome (p = 0.03). These tumours showed deregulation of genes associated with cell cycle and DNA repair biological processes. This study provides evidence that TP53 mutational analysis improves risk stratification in DAWT. This requires validation in an independent cohort before clinical use as a biomarker.

A bstract We consider pure SU(2) Yang-Mills theory on four-dimensional de Sitter dS 4 and anti-de Sitter AdS 4 spaces and construct various solutions to the Yang-Mills equations. On de Sitter space we reduce the Yang-Mills equations via an SU(2)-equivariant ansatz to Newtonian mechanics of a particle moving in ℝ 3 under the influence of a quartic potential. Then we describe magnetic and electric-magnetic solutions, both Abelian and non-Abelian, all having finite energy and finite action. A similar reduction on anti-de Sitter space also yields Yang-Mills solutions with finite energy and action. We propose a lower bound for the action on both backgrounds. Employing another metric on AdS 4 , the SU(2) Yang-Mills equations are reduced to an analytic continuation of the above particle mechanics from ℝ 3 to ℝ 2 , 1 . We discuss analytical solutions to these equations, which produce infinite-action configurations. After a Euclidean continuation of dS 4 and AdS 4 we also present self-dual (instanton-type) Yang-Mills solutions on these backgrounds.

We consider Yang–Mills theory with a compact gauge group G on Minkowski space R3,1 and compare the introduction of masses of gauge bosons using the Stueckelberg and Higgs mechanisms. The Stueckelberg field ϕ is identified with a G-frame on the gauge vector bundle E and the kinetic term for ϕ leads to the mass of the gauge bosons. The Stueckelberg mechanism is extended to the Higgs mechanism by adding to the game a scalar field describing rescaling of metric on fibres of E. Thus, we associate Higgs fields as well as running coupling parameters with conformal geometry on fibres of gauge bundles. In particular, a running coupling tending to zero or to infinity is equivalent to an unbounded expansion of G-fibres or its contraction to a point. We also discuss scale connection, space-time dependent Higgs vacua and compactly supported gauge and quark fields as an attribute of confinement.

A bstract We consider Yang-Mills theory with a compact structure group G on four-dimensional de Sitter space dS 4 . Using conformal invariance, we transform the theory from dS 4 to the finite cylinder I × S 3 , where I = ( −π/ 2 , π/ 2) and S 3 is the round three-sphere. By considering only bundles P → I × S 3 which are framed over the temporal boundary ∂ I × S 3 , we introduce additional degrees of freedom which restrict gauge transformations to be identity on ∂ I × S 3 . We study the consequences of the framing on the variation of the action, and on the Yang-Mills equations. This allows for an infinite-dimensional moduli space of Yang-Mills vacua on dS 4 . We show that, in the low-energy limit, when momentum along I is much smaller than along S 3 , the Yang-Mills dynamics in dS 4 is approximated by geodesic motion in the infinite-dimensional space M vac of gauge-inequivalent Yang-Mills vacua on S 3 . Since M vac ≅ C ∞ ( S 3 , G ) /G is a group manifold, the dynamics is expected to be integrable.

Based on new measurements of the ratio of cumulative spectra of particles fission products Pu performed at the National Research Centre Kurchatov Institute (KI), the cumulative spectra of particles fission products of U, Pu, and U isotopes are updated. The presented spectra of -particles U and Pu of KI are compared with similar spectra measured at the Institute Laue–Langevin (ILL), and the spectrum of particles fission products U of KI are compared with the measurements performed at the Technical University of Munich (TUM). It is shown that the ILL ratio of spectra of -particles U/ Pu is mistakenly overestimated by .

Inflammatory/immune cells and mediators are substantial for wound healing because they orchestrate biological activities in this complex process. Among factors that affect wound healing, obesity, and metabolic diseases are among the most significant, particularly because of a relationship between obesity and a prediabetic state with immune reactivity. Using Dark Agouti (DA) and Albino Oxford (AO) rats, which differ in immune responses as well as in proneness to obesity, we examined the impact of these intrinsic factors on cutaneous wound healing. Dynamics of the process were monitored at days 3, 5, and 7 post‐wounding parallel in both rat strains by analysis of selected basic aspects of the wound repair process (cytokine and growth factor responses) in granulation tissue. Strain‐related differences in the extent of reduction of the wound area were shown, which coincided with differential proinflammatory and immune‐regulatory cytokines, as well as growth factors response in these rats. Some of these differences seem related to their dissimilarities in the proneness to obesity. Results in this study extended so far known differences in inflammatory/immune responses to a variety of stimuli between AO and DA rats and showed, for the first time, immune‐based differences in wound healing between rats that differ in body mass (BM) and obesity proneness (under ad libitum feeding conditions with normal rodent chow).