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Goljanek-Whysall K.,University of East Anglia | Goljanek-Whysall K.,Institute of Ageing and Chronic Disease | Mok G.F.,University of East Anglia | Alrefaei A.F.,University of East Anglia | And 3 more authors.
Development (Cambridge) | Year: 2014

Myogenesis involves the stable commitment of progenitor cells followed by the execution of myogenic differentiation, processes that are coordinated by myogenic regulatory factors, microRNAs and BAF chromatin remodeling complexes. BAF60a, BAF60b and BAF60c are structural subunits of the BAF complex that bind to the core ATPase Brg1 to provide functional specificity. BAF60c is essential for myogenesis; however, the mechanisms regulating the subunit composition of BAF/Brg1 complexes, in particular the incorporation of different BAF60 variants, are not understood. Here we reveal their dynamic expression during embryo myogenesis and uncover the concerted negative regulation of BAF60a and BAF60b by the muscle-specific microRNAs (myomiRs) miR-133 and miR-1/206 during somite differentiation. MicroRNA inhibition in chick embryos leads to increased BAF60a or BAF60b levels, a concomitant switch in BAF/Brg1 subunit composition and delayed myogenesis. The phenotypes are mimicked by sustained BAF60a or BAF60b expression and are rescued by morpholino knockdown of BAF60a or BAF60b. This suggests that myomiRs contribute to select BAF60c for incorporation into the Brg1 complex by specifically targeting the alternative variants BAF60a and BAF60b during embryo myogenesis, and reveals that interactions between tissue-specific non-coding RNAs and chromatin remodeling factors confer robustness to mesodermal lineage determination. © 2014. Published by The Company of Biologists Ltd.

News Article | April 25, 2016
Site: www.biosciencetechnology.com

Researchers from the University of Liverpool have identified a specific gene that plays a key role in an inherited eye disorder. The discovery solves a 20 year-old puzzle for a family in Liverpool who all developed epithelial recurrent erosion dystrophy (ERED), a genetic corneal dystrophy disorder that causes abnormality of the outer layer of the eye. Corneal dystrophies may not cause symptoms in some individuals; in others they may cause significant vision impairment. These disorders are caused by many different genes some of which are known but many have yet to be identified. The Liverpool family, Ridland and Kadiri, first met Professor Colin Willoughby, from the University's Institute of Ageing and Chronic Disease (IACD), when he was a junior doctor and corneal fellow at St. Paul's Eye Unit in 1996. They had a type of corneal dystrophy, as yet unidentified, which caused spontaneous, recurrent, painful scratches on the cornea from early life. In discussion with New Zealand-based Opthalmologist, Dr. Andrea Vincent, Professor Willoughby learnt that there were similar families in New Zealand and Australia. Working together they sought to characterize the gene responsible for this particular disorder by using genomics. Professor Willoughby, said: "Technological advances in the clinic and laboratory have allowed us a greater appreciation of the observable physical or biochemical characteristics of an organism and the genetic diversity of corneal dystrophies. "As a result of this study we are now able to offer a genetic diagnosis of the disease before the actual symptoms of the disease have appeared. We can also give advice to parents concerning the risks associated with this disorder in a child." Epithelial recurrent erosion dystrophy (ERED) is a rare form of superficial corneal dystrophy which affects the clear window on the front of the eye. Patients develop recurrent, painful scratches on the cornea damaging its outermost layer and healing with a scar. These erosions which usually commence in childhood are painful and lead to intense light sensitivity and reduced vision. Laser treatment can help alleviate the symptoms and although this does not cure the disease it does slow it down. No treatments are available to correct the genetic defect at the present time. Lecturer in Cell and Molecular Biology at the University's Department of Eye and Vision Science (IACD), Dr Kevin Hamill, said: "The protein identified in this study is called collagen 17 and it has a pivotal role in the skin. And, from this study, the eye. Understanding the function of these types of proteins have broader implications for wound healing in the body and scarring in the eye. "This work shows the power of genomics and success of the unique research environment here at the Institute of Ageing and Chronic Disease for studying the genetics and biology of eye disease."

McDonagh B.,Institute of Ageing and Chronic Disease | Sakellariou G.K.,Institute of Ageing and Chronic Disease | Smith N.T.,Institute of Ageing and Chronic Disease | Brownridge P.,University of Liverpool | Jackson M.J.,Institute of Ageing and Chronic Disease
Journal of Proteome Research | Year: 2014

The molecular mechanisms underlying skeletal muscle aging and associated sarcopenia have been linked to an altered oxidative status of redox-sensitive proteins. Reactive oxygen and reactive nitrogen species (ROS/RNS) generated by contracting skeletal muscle are necessary for optimal protein function, signaling, and adaptation. To investigate the redox proteome of aging gastrocnemius muscles from adult and old male mice, we developed a label-free quantitative proteomic approach that includes a differential cysteine labeling step. The approach allows simultaneous identification of up-and downregulated proteins between samples in addition to the identification and relative quantification of the reversible oxidation state of susceptible redox cysteine residues. Results from muscles of adult and old mice indicate significant changes in the content of chaperone, glucose metabolism, and cytoskeletal regulatory proteins, including Protein DJ-1, cAMP-dependent protein kinase type II, 78 kDa glucose regulated protein, and a reduction in the number of redox-responsive proteins identified in muscle of old mice. Results demonstrate skeletal muscle aging causes a reduction in redox-sensitive proteins involved in the generation of precursor metabolites and energy metabolism, indicating a loss in the flexibility of the redox energy response. Data is available via ProteomeXchange with identifier PXD001054. © 2014 American Chemical Society.

Noble P.,University of Liverpool | Singer E.R.,Institute of Ageing and Chronic Disease | Jeffery N.S.,Institute of Ageing and Chronic Disease | Jeffery N.S.,University of Liverpool
Journal of Anatomy | Year: 2016

Sagittal fractures of the first phalanx are a common, potentially catastrophic injury in racehorses. These fractures are often linked to an acute, one time, biomechanical event; however, recent evidence implies that chronic exposure to stress can lead to the accumulation of bony changes that affect the structural integrity of the bone and increase the likelihood of fracture. The aim of the study was to compare variations of two common metrics of bone adaptation – subchondral bone density and thickness across the proximal articular surface of the first phalanx in Thoroughbred horses that (1) raced but never experienced a first phalanx fracture (Raced Control); (2) raced and had experienced fracture of the contralateral first phalanx (Contralateral to Fracture); (3) had never raced or experienced a first phalanx fracture (Unraced Control). A total of 22 first phalangeal bones were sampled post-mortem and imaged using micro-computed tomography calibrated for mineral density measures. Measurements of volumetric subchondral bone mineral density and thickness were taken from images at five sites from medial to lateral, in three coronal planes (25, 50 and 75% dorsal-palmar). At each of the 15 sites, measurements were repeated and averaged across 10 adjacent micro-computed tomography slices of bone, spanning 0.75 mm. The magnitude and variance of these measurements were compared between sites and between cohorts with non-parametric statistical tests. Across the proximal osteochondral surface of the first phalanx, the pattern of subchondral bone volumetric bone mineral density and thickness varied with each coronal section studied. The subchondral bone thickness was greater for the central and dorsal coronal sections, compared with the palmar section. For the race-fit groups (Raced Control and Contralateral to Fracture), the highest volumetric bone mineral density was in the central sagittal groove. The volumetric bone mineral density was significantly greater in the sagittal groove in the central coronal section in the raced than the unraced group. The Contralateral to Fracture group demonstrated significantly greater variance of volumetric bone mineral density compared with the Raced Control and Unraced Control (P < 0.0001), with no difference in variance noted between the Raced Control and Unraced Control groups. There was a small (R rank = 0.3) but significant correlation between subchondral bone volumetric bone mineral density and thickness in the Contralateral to Fracture group (P = 0.005). The findings demonstrate that differences exist in subchondral bone volumetric bone mineral density and thickness across the proximal osteochondral surface of the equine first phalanx in horses with different training histories. The findings also demonstrate that the subchondral bone of the sagittal groove of the equine first phalanx adapts to race-training in the race-fit groups (Raced Control and Contralateral to Fracture) with an increase in volumetric bone mineral density relative to unraced controls. Within the race-trained groups, the Contralateral to Fracture bones had a greater variance of volumetric bone mineral density, suggesting that stress-induced bone adaptation had become more erratic, potentially contributing to the aetiology of sagittal fractures of the first phalanx in the Thoroughbred racehorse. © 2016 Anatomical Society

West M.A.,University of Liverpool | West M.A.,Institute of Ageing and Chronic Disease | West M.A.,National Health Research Institute | Parry M.G.,University of Liverpool | And 6 more authors.
British Journal of Surgery | Year: 2014

Background This study investigated the relationship between objectively measured physical fitness variables derived by cardiopulmonary exercise testing (CPET) and in-hospital morbidity after rectal cancer surgery. Methods Patients scheduled for rectal cancer surgery underwent preoperative CPET (reported blind to patient characteristics) with recording of morbidity (recorded blind to CPET variables). Non-parametric receiver operating characteristic (ROC) curves and logistic regression were used to assess the relationship between CPET variables and postoperative morbidity. Results Of 105 patients assessed, 95 (72 men) were included; ten patients had no surgery and were excluded (3 by choice, 7 owing to unresectable metastasis). Sixty-eight patients had received neoadjuvant treatment. ROC curve analysis of oxygen uptake (VËo2) at estimated lactate threshold (θ^L) and peak VËo2 gave an area under the ROC curve of 0·87 (95 per cent confidence interval 0·78 to 0·95; P < 0·001) and 0·85 (0·77 to 0·93; P < 0·001) respectively, indicating that they can help discriminate patients at risk of postoperative morbidity. The optimal cut-off points identified were 10·6 and 18·6 ml per kg per min for VËo2 at θ^L and peak respectively. Conclusion CPET can help predict morbidity after rectal cancer surgery. Practical, useful and worthwhile © 2014 BJS Society Ltd. Published by John Wiley & Sons Ltd.

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