Oxytocin is an age-specific circulating hormone that is necessary for muscle maintenance and regeneration.

The regenerative capacity of skeletal muscle declines with age. Previous studies suggest that this process can be reversed by exposure to young circulation; however, systemic age-specific factors responsible for this phenomenon are largely unknown. Here we report that oxytocin--a hormone best known for its role in lactation, parturition and social behaviours--is required for proper muscle tissue regeneration and homeostasis, and that plasma levels of oxytocin decline with age. Inhibition of oxytocin signalling in young animals reduces muscle regeneration, whereas systemic administration of oxytocin rapidly improves muscle regeneration by enhancing aged muscle stem cell activation/proliferation through activation of the MAPK/ERK signalling pathway. We further show that the genetic lack of oxytocin does not cause a developmental defect in muscle but instead leads to premature sarcopenia. Considering that oxytocin is an FDA-approved drug, this work reveals a potential novel and safe way to combat or prevent skeletal muscle ageing

Low-cell-number, single-tube amplification (STA) of total RNA revealed transcriptome changes from pluripotency to endothelium

Table S1. Summary of the sequencing results. The alignments against the GRCh38 genome assembly (Aligned Reads) were counted for exon reads (exon) and transcript reads based on GENCODE v22. Intronic counts (intron) were defined by transcript counts minus exon ones. Nontranscript reads were used to obtain tRNA counts (tRNA) based on the tRNA database of GENCODE v22. Nontranscript and non-tRNA reads were used for counts on repetitive sequences (repeats) based on RepeatMasker. Those not belonging to any category were defined as unannotated reads (unannotated). The counting of exonic features was based on the “gene_type” attribute in GENCODE v22. The percentages of mature miRNA reads were defined by reads aligned exclusively to the mature “miRNA” feature divided by reads aligned to the “miRNA_primary_transcript” feature of miRBase v21. (DOCX 42 kb

Exploiting buck–boost duality in dual active bridge modular multilevel converters to achieve high DC step ratios

Abstract A previously unidentified duality between buck and boost configured dc‐ac modular multilevel converters (MMCs) is firstly revealed. Armed with this insight, a new dual‐active‐bridge (DAB)‐MMC is proposed for high‐voltage dc (HVDC)‐to‐medium‐voltage dc (MVDC) power conversion that utilizes cascaded buck and boost dc–ac stages to obtain high dc step ratios. Single‐phase and three‐phase variants are presented. When compared with the conventional DAB‐MMC solution for the same dc step ratio, both the single‐phase and three‐phase topologies offer reduced MVDC side transformer winding current stresses, while the three‐phase topology also yields reduced MVDC side MMC submodule current stresses. The former is achieved by having the freedom to design the transformer with a lower turns ratio, and the latter is achieved due to the inherent paralleling of submodules on the MVDC side of the converter. Analysis of the three‐phase topology reveals its low‐voltage side transformer winding current stresses can be reduced by a factor of 3.27. A generalized mathematical model of the proposed buck–boost DAB‐MMC is derived and used to propose a dynamic controller for both the single‐phase and three‐phase topologies. Real‐time simulations obtained from a real‐time digital simulator system that incorporates an FPGA‐based controller for the valve firing controls validate the proposed buck–boost DAB‐MMC operation and dynamic controls

EVALUATING MODEL UNCERTAINTY OF AN SPT-BASED SIMPLIFIED METHOD FOR RELIABILITY ANALYSIS FOR PROBABILITY OF LIQUEFACTION

In this paper, an innovative procedure is developed for estimating the uncertainty of an empirical geotechnical model. Here, the Youd et al. (2001) method, a deterministic model for liquefaction triggering evaluation, is examined for its model uncertainty. The procedure for evaluating this model uncertainty involves two steps: 1) deriving a Bayesian mapping function based on a database of case histories, and 2) using the calibrated Bayesian mapping function as a reference to back-figure the uncertainty of the model. Details of the developed procedure within the framework of the first-order reliability method (FORM) are presented. Using FORM with the calibrated model uncertainty, the probability of liquefaction can be readily determined, and thus, the results presented in this paper extend the use of the Youd et al. (2001) method

Regenerative capacity of old muscle stem cells declines without significant accumulation of DNA damage.

The performance of adult stem cells is crucial for tissue homeostasis but their regenerative capacity declines with age, leading to failure of multiple organs. In skeletal muscle this failure is manifested by the loss of functional tissue, the accumulation of fibrosis, and reduced satellite cell-mediated myogenesis in response to injury. While recent studies have shown that changes in the composition of the satellite cell niche are at least in part responsible for the impaired function observed with aging, little is known about the effects of aging on the intrinsic properties of satellite cells. For instance, their ability to repair DNA damage and the effects of a potential accumulation of DNA double strand breaks (DSBs) on their regenerative performance remain unclear. This work demonstrates that old muscle stem cells display no significant accumulation of DNA DSBs when compared to those of young, as assayed after cell isolation and in tissue sections, either in uninjured muscle or at multiple time points after injury. Additionally, there is no significant difference in the expression of DNA DSB repair proteins or globally assayed DNA damage response genes, suggesting that not only DNA DSBs, but also other types of DNA damage, do not significantly mark aged muscle stem cells. Satellite cells from DNA DSB-repair-deficient SCID mice do have an unsurprisingly higher level of innate DNA DSBs and a weakened recovery from gamma-radiation-induced DNA damage. Interestingly, they are as myogenic in vitro and in vivo as satellite cells from young wild type mice, suggesting that the inefficiency in DNA DSB repair does not directly correlate with the ability to regenerate muscle after injury. Overall, our findings suggest that a DNA DSB-repair deficiency is unlikely to be a key factor in the decline in muscle regeneration observed upon aging

Oxytocin is an age-specific circulating hormone that is necessary for muscle maintenance and regeneration.

The regenerative capacity of skeletal muscle declines with age. Previous studies suggest that this process can be reversed by exposure to young circulation; however, systemic age-specific factors responsible for this phenomenon are largely unknown. Here we report that oxytocin--a hormone best known for its role in lactation, parturition and social behaviours--is required for proper muscle tissue regeneration and homeostasis, and that plasma levels of oxytocin decline with age. Inhibition of oxytocin signalling in young animals reduces muscle regeneration, whereas systemic administration of oxytocin rapidly improves muscle regeneration by enhancing aged muscle stem cell activation/proliferation through activation of the MAPK/ERK signalling pathway. We further show that the genetic lack of oxytocin does not cause a developmental defect in muscle but instead leads to premature sarcopenia. Considering that oxytocin is an FDA-approved drug, this work reveals a potential novel and safe way to combat or prevent skeletal muscle ageing

Regenerative Capacity of Old Muscle Stem Cells Declines without Significant Accumulation of DNA Damage

<div><p>The performance of adult stem cells is crucial for tissue homeostasis but their regenerative capacity declines with age, leading to failure of multiple organs. In skeletal muscle this failure is manifested by the loss of functional tissue, the accumulation of fibrosis, and reduced satellite cell-mediated myogenesis in response to injury. While recent studies have shown that changes in the composition of the satellite cell niche are at least in part responsible for the impaired function observed with aging, little is known about the effects of aging on the intrinsic properties of satellite cells. For instance, their ability to repair DNA damage and the effects of a potential accumulation of DNA double strand breaks (DSBs) on their regenerative performance remain unclear. This work demonstrates that old muscle stem cells display no significant accumulation of DNA DSBs when compared to those of young, as assayed after cell isolation and in tissue sections, either in uninjured muscle or at multiple time points after injury. Additionally, there is no significant difference in the expression of DNA DSB repair proteins or globally assayed DNA damage response genes, suggesting that not only DNA DSBs, but also other types of DNA damage, do not significantly mark aged muscle stem cells. Satellite cells from DNA DSB-repair-deficient SCID mice do have an unsurprisingly higher level of innate DNA DSBs and a weakened recovery from gamma-radiation-induced DNA damage. Interestingly, they are as myogenic <i>in vitro</i> and <i>in vivo</i> as satellite cells from young wild type mice, suggesting that the inefficiency in DNA DSB repair does not directly correlate with the ability to regenerate muscle after injury. Overall, our findings suggest that a DNA DSB-repair deficiency is unlikely to be a key factor in the decline in muscle regeneration observed upon aging.</p></div