Molecular networks of human muscle adaptation to exercise and age

Physical activity and molecular ageing presumably interact to precipitate musculoskeletal decline in humans with age. Herein, we have delineated molecular networks for these two major components of sarcopenic risk using multiple independent clinical cohorts. We generated genome-wide transcript profiles from individuals (n = 44) who then undertook 20 weeks of supervised resistance-exercise training (RET). Expectedly, our subjects exhibited a marked range of hypertrophic responses (3% to +28%), and when applying Ingenuity Pathway Analysis (IPA) up-stream analysis to ~580 genes that co-varied with gain in lean mass, we identified rapamycin (mTOR) signaling associating with growth (P = 1.4×10−30). Paradoxically, those displaying most hypertrophy exhibited an inhibited mTOR activation signature, including the striking down-regulation of 70 rRNAs. Differential analysis found networks mimicking developmental processes (activated all-trans-retinoic acid (ATRA, Z-score = 4.5; P = 6×10−13) and inhibited aryl-hydrocarbon receptor signaling (AhR, Z-score = −2.3; P = 3×10−7)) with RET. Intriguingly, as ATRA and AhR gene-sets were also a feature of endurance exercise training (EET), they appear to represent “generic” physical activity responsive gene-networks. For age, we found that differential gene-expression methods do not produce consistent molecular differences between young versus old individuals. Instead, utilizing two independent cohorts (n = 45 and n = 52), with a continuum of subject ages (18–78 y), the first reproducible set of age-related transcripts in human muscle was identified. This analysis identified ~500 genes highly enriched in post-transcriptional processes (P = 1×10−6) and with negligible links to the aforementioned generic exercise regulated gene-sets and some overlap with ribosomal genes. The RNA signatures from multiple compounds all targeting serotonin, DNA topoisomerase antagonism, and RXR activation were significantly related to the muscle age-related genes. Finally, a number of specific chromosomal loci, including 1q12 and 13q21, contributed by more than chance to the age-related gene list (P = 0.01–0.005), implying possible epigenetic events. We conclude that human muscle age-related molecular processes appear distinct from the processes regulated by those of physical activity

The importance of the cellular stress response in the pathogenesis and treatment of type 2 diabetes

Organisms have evolved to survive rigorous environments and are not prepared to thrive in a world of caloric excess and sedentary behavior. A realization that physical exercise (or lack of it) plays a pivotal role in both the pathogenesis and therapy of type 2 diabetes mellitus (t2DM) has led to the provocative concept of therapeutic exercise mimetics. A decade ago, we attempted to simulate the beneficial effects of exercise by treating t2DM patients with 3 weeks of daily hyperthermia, induced by hot tub immersion. The short-term intervention had remarkable success, with a 1 % drop in HbA1, a trend toward weight loss, and improvement in diabetic neuropathic symptoms. An explanation for the beneficial effects of exercise and hyperthermia centers upon their ability to induce the cellular stress response (the heat shock response) and restore cellular homeostasis. Impaired stress response precedes major metabolic defects associated with t2DM and may be a near seminal event in the pathogenesis of the disease, tipping the balance from health into disease. Heat shock protein inducers share metabolic pathways associated with exercise with activation of AMPK, PGC1-a, and sirtuins. Diabetic therapies that induce the stress response, whether via heat, bioactive compounds, or genetic manipulation, improve or prevent all of the morbidities and comorbidities associated with the disease. The agents reduce insulin resistance, inflammatory cytokines, visceral adiposity, and body weight while increasing mitochondrial activity, normalizing membrane structure and lipid composition, and preserving organ function. Therapies restoring the stress response can re-tip the balance from disease into health and address the multifaceted defects associated with the disease

Valorisation of Biowastes for the Production of Green Materials Using Chemical Methods

With crude oil reserves dwindling, the hunt for a sustainable alternative feedstock for fuels and materials for our society continues to expand. The biorefinery concept has enjoyed both a surge in popularity and also vocal opposition to the idea of diverting food-grade land and crops for this purpose. The idea of using the inevitable wastes arising from biomass processing, particularly farming and food production, is, therefore, gaining more attention as the feedstock for the biorefinery. For the three main components of biomass—carbohydrates, lipids, and proteins—there are long-established processes for using some of these by-products. However, the recent advances in chemical technologies are expanding both the feedstocks available for processing and the products that be obtained. Herein, this review presents some of the more recent developments in processing these molecules for green materials, as well as case studies that bring these technologies and materials together into final products for applied usage

The use of electronic detonators to access additional aggregate reserves adjacent to subsurface structures

A number of theoretical papers have been published outlining the use of electronic detonators to limit peak particle vibrations levels, but few empirical studies have been undertaken and even fewer examples have been published of the use of such technology in the aggregates industry. This paper gives a summary of the research work carried out at two limestone quarries in the North of England, where a series of blasts were used to compare and contrast the use of electronic and non-electric detonators. The majority of blasts were carried out using the same burden, spacing and decked charge weight loadings. A methodology was established that could be used to reduce the peak particle velocities (PPVs) at two or more specific locations by using single-hole blast vibration signatures in conjunction with specific electronic detonator timing intervals. The initial study concluded that this was only possible if single-hole signature blasts were periodically recorded to establish the shape of the correct vibration envelopes as properties were approached. These wave envelopes could then be used as the basis for choosing the specific electronic detonator timing intervals to give the lowest PPV for the properties or locations concerned. This methodology was then used in the second study to access a large volume of aggregates adjacent to a working railway tunnel. The financial benefit f

Investigation to Determine the Origin of Air Overpressure from Quarry Blasting

Previous researchers have put forward two different theories as to the origin of air overpressure from quarry blasting. In 1980, Siskind et al. postulated that the initial face movement gave rise to the displacement of air and that this resulted in the air overpressure pulse. However in 1990 McKenzie et al. carried out research that indicated that the air overpressure pulse came into being as consequence of the shock wave created by the detonation of the explosive charge in a blast hole, rapidly propagating through the rock and then impacting on the quarry face. In an attempt to evaluate these opposing hypotheses, an investigation was undertaken over a 4-year period with the aim of determining the precise origin of air overpressure. The research was carried out at a chalk quarry in the North of England. The choice of this particular location was made on the basis that the rock type is very homogeneous with no discontinuities and the quarry operator carries out small full scale single row blast (typically five holes per blast). Thus a series of tests using single row fully instrumented full scale quarry blasts were carried out. The components that were assessed and investigated were the air blast arrival times in front of the face, the initial movement of the blast face, the precise initiation times of each blast hole, the speed of sound in both air and the rock host and an attempt was made at timing the development of the peak gas pressure within the blast holes. The investigation indicated that the event (within the blast mechanism that is the source of air overpressure) always occurred sometime after the Shockwave had impacted the face but on average before initial face movement. This lead to the conclusion that it was most likely that the transmission of gas through the face, created from the detonation of the explosive charge was the source of air overpressure. However it must be borne in mind that these air overpressure experiments have only been carried out on one specific rock type

Secure accommodation in Hampshire A review 1993-1994

SIGLEAvailable from British Library Document Supply Centre- DSC:7761.855(HSS-RR--78) / BLDSC - British Library Document Supply CentreGBUnited Kingdo