Mammalian genes induce partially reprogrammed pluripotent stem cells in non-mammalian vertebrate and invertebrate species.

Cells are fundamental units of life, but little is known about evolution of cell states. Induced pluripotent stem cells (iPSCs) are once differentiated cells that have been re-programmed to an embryonic stem cell-like state, providing a powerful platform for biology and medicine. However, they have been limited to a few mammalian species. Here we found that a set of four mammalian transcription factor genes used to generate iPSCs in mouse and humans can induce a partially reprogrammed pluripotent stem cell (PRPSCs) state in vertebrate and invertebrate model organisms, in mammals, birds, fish, and fly, which span 550 million years from a common ancestor. These findings are one of the first to show cross-lineage stem cell-like induction, and to generate pluripotent-like cells for several of these species with in vivo chimeras. We suggest that the stem-cell state may be highly conserved across a wide phylogenetic range. DOI:http://dx.doi.org/10.7554/eLife.00036.001

Energy flow analysis of amputee walking shows a proximally-directed transfer of energy in intact limbs, compared to a distally-directed transfer in prosthetic limbs at push-off

Reduced capacity and increased metabolic cost of walking occurs in amputees, despite advances in prosthetic componentry. Joint powers can quantify deficiencies in prosthetic gait, but do not reveal how energy is exchanged between limb segments. This study aimed to quantify these energy exchanges during amputee walking. Optical motion and forceplate data collected during walking at a self-selected speed for cohorts of 10 controls, 10 unilateral trans-tibial, 10 unilateral trans-femoral and 10 bilateral trans-femoral amputees were used to determine the energy exchanges between lower limb segments. At push-off, consistent thigh and shank segment powers were observed between amputee groups (1.12W/kg vs. 1.05W/kg for intact limbs and 0.97W/kg vs. 0.99W/kg for prosthetic limbs), and reduced prosthetic ankle power, particularly in trans-femoral amputees (3.12W/kg vs. 0.87W/kg). Proximally-directed energy exchange was observed in the intact limbs of amputees and controls, while prosthetic limbs displayed distally-directed energy exchanges at the knee and hip. This study used energy flow analysis to show a reversal in the direction in which energy is exchanged between prosthetic limb segments at push-off. This reversal was required to provide sufficient energy to propel the limb segments and is likely a direct result of the lack of push-off power at the prosthetic ankle, particularly in trans-femoral amputees, and leads to their increased metabolic cost of walking

Introduction: looking beyond the walls

In its consideration of the remarkable extent and variety of non-university researchers, this book takes a broader view of ‘knowledge’ and ‘research’ than in the many hot debates about today’s knowledge society, ‘learning age’, or organisation of research. It goes beyond the commonly held image of ‘knowledge’ as something produced and owned by the full-time experts to take a look at those engaged in active knowledge building outside the university walls

Neonatal-onset multisystem inflammatory disease responsive to interleukin-1 beta inhibition

BACKGROUND:Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation. Many patients have mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene, encoding cryopyrin, a protein that regulates inflammation.METHODS:We selected 18 patients with neonatal-onset multisystem inflammatory disease (12 with identifiable CIAS1 mutations) to receive anakinra, an interleukin-1-receptor antagonist (1 to 2 mg per kilogram of body weight per day subcutaneously). In 11 patients, anakinra was withdrawn at three months until a flare occurred. The primary end points included changes in scores in a daily diary of symptoms, serum levels of amyloid A and C-reactive protein, and the erythrocyte sedimentation rate from baseline to month 3 and from month 3 until a disease flare.RESULTS:All 18 patients had a rapid response to anakinra, with disappearance of rash. Diary scores improved (P<0.001) and serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3 (all P<0.001), and remained low at month 6. Magnetic resonance imaging showed improvement in cochlear and leptomeningeal lesions as compared with baseline. Withdrawal of anakinra uniformly resulted in relapse within days; retreatment led to rapid improvement. There were no drug-related serious adverse events.CONCLUSIONS:Daily injections of anakinra markedly improved clinical and laboratory manifestations in patients with neonatal-onset multisystem inflammatory disease, with or without CIAS1 mutations

A qualitative study of enablers and barriers influencing the incorporation of social accountability values into organisational culture: a perspective from two medical schools

Background: Definitions of social accountability describe the obligation of medical schools to direct education, research and service activities towards addressing the priority health concerns of the population they serve. While such statements give some direction as to how the goal might be reached, it does not identify what factors might facilitate or hinder its achievement. This study set out to identify and explore enablers and barriers influencing the incorporation of social accountability values into medical schools. Methods: Semi structured interviews of fourteen senior staff in Bar Ilan and Leeds medical schools were undertaken following a literature review. Participants were recruited by purposive sampling in order to identify factors perceived to play a part in the workings of each institution. Results: Academic prestige was seen as a key barrier that was dependent on research priorities and student selection. The role of champions was considered to be vital to tackle staff perceptions and facilitate progress. Including practical community experience for students was felt to be a relevant way in which the curriculum could be designed through engagement with local partners. Conclusions: Successful adoption of social accountability values requires addressing concerns around potential negative impacts on academic prestige and standards. Identifying and supporting credible social accountability champions to disseminate the values throughout research and education departments in medical and other faculties is also necessary, including mapping onto existing work streams and research agendas. Demonstrating the contribution the institution can make to local health improvement and regional development by a consideration of its economic footprint may also be valuable

Mechanical loading of bioengineered skeletal muscle in vitro recapitulates gene expression signatures of resistance exercise in vivo.

Understanding the role of mechanical loading and exercise in skeletal muscle (SkM) is paramount for delineating the molecular mechanisms that govern changes in muscle mass. However, it is unknown whether loading of bioengineered SkM in vitro adequately recapitulates the molecular responses observed after resistance exercise (RE) in vivo. To address this, the transcriptional and epigenetic (DNA methylation) responses were compared after mechanical loading in bioengineered SkM in vitro and after RE in vivo. Specifically, genes known to be upregulated/hypomethylated after RE in humans were analyzed. Ninety-three percent of these genes demonstrated similar changes in gene expression post-loading in the bioengineered muscle when compared to acute RE in humans. Furthermore, similar differences in gene expression were observed between loaded bioengineered SkM and after programmed RT in rat SkM tissue. Hypomethylation occurred for only one of the genes analysed (GRIK2) post-loading in bioengineered SkM. To further validate these findings, DNA methylation and mRNA expression of known hypomethylated and upregulated genes post-acute RE in humans were also analyzed at 0.5, 3, and 24 h post-loading in bioengineered muscle. The largest changes in gene expression occurred at 3 h, whereby 82% and 91% of genes responded similarly when compared to human and rodent SkM respectively. DNA methylation of only a small proportion of genes analyzed (TRAF1, MSN, and CTTN) significantly increased post-loading in bioengineered SkM alone. Overall, mechanical loading of bioengineered SkM in vitro recapitulates the gene expression profile of human and rodent SkM after RE in vivo. Although some genes demonstrated differential DNA methylation post-loading in bioengineered SkM, such changes across the majority of genes analyzed did not closely mimic the epigenetic response to acute-RE in humans

UBR5 is a Novel E3 Ubiquitin Ligase involved in Skeletal Muscle Hypertrophy and Recovery from Atrophy

We have recently identified that a HECT domain E3 ubiquitin ligase, named UBR5, was epigenetically altered (via DNA methylation) after human skeletal muscle hypertrophy, where its gene expression was positively correlated with increased lean leg mass in humans [1]. This was counterintuitive given the well-defined role of other E3 ligase family members, MuRF1 and MAFbx in muscle atrophy. Therefore, in the present study we aimed to investigate this relatively uncharacterised E3 ubiquitin ligase using multiple in-vivo and in-vitro models of skeletal muscle atrophy, injury, recovery from atrophy as well as anabolism and hypertrophy. We report for the first time, that during atrophy evoked by tetrodotoxin (TTX) nerve silencing in rats, the UBR5 promoter was significantly hypomethylated with a concomitant increase in gene expression early (3 & 7 days) after the induction of atrophy. However, at these timepoints larger increases in MuRF1/MAFbx were observed, and UBR5 expression had returned to baseline levels during later atrophy (14 days) where muscle mass loss was greatest. We confirmed an alternate gene expression profile for UBR5 versus MuRF1/MAFbx in a secondary model of atrophy induced by 7 days continuous low frequency electrical stimulation, where UBR5 demonstrated no significant increase, whereas MuRF1/MAFbx were elevated. Further, after partial (52%) recovery of muscle mass following 7 days TTX-cessation, UBR5 was hypomethylated and increased at the gene expression level, while alternately, reductions in gene expression of MuRF1 and MAFbx were observed. To substantiate these gene expression findings, we observed a significant increase in UBR5 protein abundance after full recovery (14 days) of muscle mass from hindlimb unloading (HU) in rats. Aged rats also demonstrated a similar temporal increase in UBR5 protein abundance after recovery from HU. Further, we confirmed significant increases in UBR5 protein during recovery from nerve crush injury in mice at 28 and 45 days, that related to a full recovery of muscle mass between 45-60 days. During anabolism and hypertrophy, UBR5 gene expression increased following an acute bout of mechanical loading in three-dimensional bioengineered mouse muscle in-vitro, and after chronic electrical stimulation-induced hypertrophy in rats in-vivo, without increases in MuRF1/MAFbx. Additionally, increased UBR5 protein abundance was identified following synergist ablation/functional overload (FO)-induced hypertrophy of the plantaris muscle in mice in-vivo, and finally over a 7-day time-course of regeneration in primary human muscle cells in-vitro. Finally, genetic association studies (> 700,000 SNPs) in human cohorts identified that the A alleles of rs10505025 and rs4734621 SNPs were strongly associated with larger cross-sectional area of fast-twitch muscle fibres and favoured strength/power versus endurance/untrained phenotypes. Overall, we suggest that UBR5 is a novel E3 ubiquitin ligase that is alternatively regulated compared to MuRF1/MAFbx, and is elevated during early atrophy (but not later atrophy), recovery, anabolism and hypertrophy in animals in-vivo as well as during human muscle cell regeneration in-vitro. In humans, genetic variations of the UBR5 gene are strongly associated with larger fast-twitch muscle fibres and strength/power performance