Simon W. Jones

Disuse atrophy and exercise rehabilitation in humans profoundly affects the expression of genes associated with the regulation of skeletal muscle mass.

Skeletal muscle atrophy occurs as a consequence of injury, illness, surgery, and muscle disuse, impacting appreciably on health care costs and patient quality of life, particularly in the absence of appropriate rehabilitation. The molecular mechanisms that regulate muscle mass during atrophy and rehabilitation in humans have not been elucidated, despite several robust candidate pathways being identified. Here, we induced skeletal muscle atrophy in healthy volunteers using two weeks of limb immobilization, and then stimulated the restoration of muscle mass with six weeks of supervised exercise rehabilitation. We determined muscle mass and function and performed targeted gene expression analysis at prescribed time points during immobilization and rehabilitation. For the first time, we have identified novel changes in gene expression following immobilization‐induced atrophy and during a program of rehabilitative exercise that restored muscle mass and function. Furthermore, we have shown that exercise performed immediately following immobilization induces profound changes in the expression of a number of genes in favor of the restoration of muscle mass, within 24 h. This information will be of considerable importance to our understanding of how immobilization and contraction stimulate muscle atrophy and hypertrophy, respectively, and to the development of novel therapeutic strategies aimed at maintaining or restoring muscle mass.

Characterisation of cell-penetrating peptide-mediated peptide delivery

1 Cell‐penetrating peptides such as antennapedia, TAT, transportan and polyarginine have been extensively employed for in vitro and in vivo delivery of biologically active peptides. However, little is known of the relative efficacy, toxicity and uptake mechanism of individual protein transduction domain–peptide conjugates, factors that will be critical in determining the most effective sequence. 2 In the present study, we show by FACS analysis that unconjugated antennapedia, TAT, transportan and polyarginine demonstrate similar kinetic uptake profiles, being maximal at 1–3 h and independent of cell type (HeLa, A549 and CHO cell lines). A comparison of the magnitude of uptake of cell‐penetrating peptide conjugates demonstrated that polyarginine=transportan>antennapedia>TAT. 3 However, examination of cellular toxicity showed that antennapedia

The identification of differentially expressed microRNA in osteoarthritic tissue that modulate the production of TNF-alpha and MMP13.

OBJECTIVE To identify differentially expressed microRNAs (miRNAs) in human osteoarthritic (OA) cartilage and bone tissue and to determine their relevance to chondrocyte function. METHODS Cartilage and bone was obtained from OA patients who underwent total knee joint replacement surgery or from post-mortem patients with no previous history of OA. MiRNA expression was quantified by real-time PCR (RT-PCR). Functional pathway analysis of miRNA was performed using Ingenuity Pathway Analysis. Primary chondrocytes were isolated by collagenase digestion and transfected with miRNA mimics and miRNA inhibitors using cationic lipid. Tumour Necrosis Factor-alpha (TNF-alpha) and Matrix metalloprotease 13 (MMP13) protein levels were measured by Enzyme-Linked ImmunoSorbent Assay (ELISA). RESULTS In total we identified 17 miRNA that showed greater than 4-fold differential expression between OA and normal cartilage, and 30 miRNA that showed greater than 4-fold differential expression in OA bone. Functional pathway analysis of the predicted gene targets for miR-9, miR-98, which were upregulated in both OA bone and cartilage tissue, and miR-146, which was downregulated in OA cartilage, suggested that these miRNA mediate inflammatory functions and pathways. Over-expression of miR-9, miR-98 or miR-146 in isolated human chondrocytes reduced interleukin-1 beta (IL-1 beta) induced TNF-alpha production. Furthermore, inhibition and over-expression of miR-9 modulated MMP13 secretion. CONCLUSIONS We have identified a number of differentially expressed miRNAs in late-stage human OA cartilage and bone. Functional analysis of miR-9, miR-98 and miR-146 in primary chondrocytes suggests a role in mediating the IL-1 beta induced production of TNF-alpha. MiR-9, upregulated in OA tissue, was found to inhibit secretion of the collagen type II-targeting metalloproteinase MMP13 in isolated human chondrocytes.

Design and performance of a main memory hardware data compressor

In this paper we show that hardware main memory data compression is both feasible and worthwhile. We demonstrate that paging due to insufficient memory resources can reduce system performance several fold, and argue that hardware memory compression can eliminate this paging hence providing a substantial performance improvement. We describe the design and implementation of a novel compression method, the X-Match algorithm, which is efficient at compressing small blocks of data and suitable for high-speed hardware implementation. Our experimental investigation shows that on average the X-Match algorithm doubles the memory capacity for commonly used Unix applications. Furthermore, the substantial impact such memory compression has on overall system performance is demonstrated.

Temporal relationship between serum adipokines, biomarkers of bone and cartilage turnover, and cartilage volume loss in a population with clinical knee osteoarthritis

OBJECTIVE The association of obesity with both hand and knee osteoarthritis (OA) is suggestive of a link between dysfunctional metabolism and joint integrity. Given the role of adipokines in mediating bone and cartilage homeostasis, we undertook this study to examine the relationship between adipokines and bone and cartilage biomarkers in a population of subjects with OA, and to determine whether adipokine levels predicted 2-year cartilage integrity. METHODS One hundred seventeen subjects underwent magnetic resonance imaging at baseline and at 2-year followup. Cartilage volume was assessed from these images. Serum adipokine levels were measured at baseline. Bone and cartilage biomarker levels were measured at baseline and at 2-year followup. Linear regression was used to examine the relationship between baseline levels of adipokines and adipokine receptors (leptin, soluble leptin receptor [sOB-Rb], resistin, and adiponectin) and changes in levels of bone biomarkers (osteocalcin, N-terminal type I procollagen propeptide [PINP], C-terminal crosslinking telopeptide of type I collagen, N-terminal crosslinking telopeptide of type I collagen, or C-terminal crosslinking telopeptide of type I collagen generated by matrix metalloproteinases), levels of cartilage biomarkers (cartilage oligomeric matrix protein, N-terminal type IIA procollagen propeptide [PIIANP], or C2C), cartilage defects score, and cartilage volume over 2 years. RESULTS Baseline leptin was associated with increased levels of bone formation biomarkers (osteocalcin and PINP) over 2 years, while sOB-Rb was associated with reduced levels of osteocalcin. Baseline sOB-Rb was associated with reduced levels of the cartilage formation biomarker PIIANP, an increased cartilage defects score, and increased cartilage volume loss over 2 years. All results were independent of age, sex, and body mass index. CONCLUSION The findings of this study support the concept that serum adipokines may provide a nonmechanical link between obesity and joint integrity (which may be mediated by bone and cartilage turnover) that subsequently results in changes to the cartilage defects score and cartilage volume loss. This may facilitate our understanding of the mechanisms by which obesity is involved in the pathogenesis of OA.

The relationship between slow and fast myosin heavy chain content, calpastatin and meat tenderness in different ovine skeletal muscles.

The present study investigated the relationship between fibre type distribution and slow (MHC-s) and fast (MHC-f) myosin heavy chain content on calpastatin and meat tenderness in longissimus dorsi (LD), tensor fasciae latae (TFL), semitendinosus (ST), trapezius (TZ) and supraspinatus (SS) muscles from six Mule×Charolais rams. Samples taken at slaughter were frozen either in liquid N(2) for analysis of MHC-s and MHC-f by immunoblotting, or in cooled isopentane for histochemical fibre typing. Calpastatin activity and an immunoreactive 135 kDa calpastatin band were analysed in samples taken 24 h postmortem. Shear force was determined on muscle chops taken at 24 h postmortem and conditioned until day 14. The intensity of MHC-s and MHC-f immunopositive bands correlated with %Type I and %Type II fibres identified histochemically (r(2)=0.612 and 0.366, respectively, p<0.001). Muscle specific differences were observed in MHC-s and MHC-f immunoreactivity, fibre type distribution, calpastatin activity, calpastatin 135 kDa immunoreactivity and shear force. MHC-s correlated positively with calpastatin activity (r(2)=0.725, p<0.001) and 135 kDa calpastatin (r(2)=0.228, p<0.01) across all muscle types. The data show that detection of MHC-s can be used to identify fibre type differences between ovine muscles and that this correlates with differences in calpastatin content and inhibitory activity, but not tenderness.

Performance evaluation of computer architectures with main memory data compression

In this paper we investigate the application of data compression to the main memory of current workstation architectures. We propose an organisation where data and code are stored in compressed form while there is competition for memory resources. Main memory data compression allows programs with working sets much greater than physical memory to execute efficiently without resorting to costly disk paging activity. A performance model for this architecture clearly demonstrates that system performance may be improved by up to a factor of two when using software based memory compression instead of paging, while hardware assisted memory compression can improve performance by up to an order of magnitude.

Memory Management in Flash-Memory Disks with Data Compression

This paper describes the design and implementation of a memory management method, Link-Fit, which allows transparent hardware data compression to be incorporated in a flash-memory based disk. Link-Fit is compared with the standard method for flash-memory management, which writes sequentially and uses copying compaction for storage reclamation. Flash-memory is different from DRAM on three accounts, it is non-volatile, it must be explicitly erased on a block basis before it can be rewritten, and it has a relatively low write performance. Data compression can improve the effective capacity, and hence the

Long Intergenic Noncoding RNAs Mediate the Human Chondrocyte Inflammatory Response and Are Differentially Expressed in Osteoarthritis Cartilage

/MB ratio by a factor of two. Likewise the write performance can be improved by a factor of two, since only half the amount of data must be written to the non-volatile store. As a result of using data compression the memory manager must handle variable sized blocks efficiently, in terms of both time overheads and storage utilisation.

Mitogen-activated protein kinase-activated protein kinase 2 (MK2) modulates key biological pathways associated with OA disease pathology

To identify long noncoding RNAs (lncRNAs), including long intergenic noncoding RNAs (lincRNAs), antisense RNAs, and pseudogenes, associated with the inflammatory response in human primary osteoarthritis (OA) chondrocytes and to explore their expression and function in OA.