GEF-H1-RhoA signaling pathway mediates LPS-induced NF-κB transactivation and IL-8 synthesis in endothelial cells

Secretion of proinflammatory cytokines by LPS activated endothelial cells contributes substantially to the pathogenesis of sepsis. However, the mechanism involved in this process is not well understood. In the present study, we determined the roles of GEF-H1 (Guanine-nucleotide exchange factor-H1)-RhoA signalling in LPS-induced interleukin-8 (IL-8, CXCL8) production in endothelial cells. First, we observed that GEF-H1 expression was upregulated in a dose- and time-dependent manner as consistent with TLR4 (Toll-like receptor 4) expression after LPS stimulation. Afterwards, Clostridium difficile toxin B-10463 (TcdB-10463), an inhibitor of Rho activities, reduced LPS-induced NF-κB phosphorylation. Inhibition of GEF-H1 and RhoA expression reduced LPS-induced NF-κB and p38 phosphorylation. TLR4 knockout blocked LPS-induced activity of RhoA, however, MyD88 knockout did not impair the LPS-induced activity of RhoA. Nevertheless, TLR4 and MyD88 knockout both significantly inhibited transactivation of NF-κB. GEF-H1-RhoA and MyD88 both induced significant changes in NF-κB transactivation and IL-8 synthesis. Co-inhibition of GEF-H1-RhoA and p38 expression produced similar inhibitory effects on LPS-induced NF-κB transactivation and IL-8 synthesis as inhibition of p38 expression alone, thus confirming that activation of p38 was essential for the GEF-H1-RhoA signalling pathway to induce NF-κB transactivation and IL-8 synthesis. Taken together, these results demonstrate that LPS-induced NF-κB activation and IL-8 synthesis in endothelial cells are regulated by the MyD88 pathway and GEF-H1-RhoA pathway.

Lateral impact response and parametric studies of axially loaded square concrete filled steel tube columns

This paper presents a numerical study on the response of axially loaded slender square concrete filled steel tube (CFST) columns under low velocity lateral impact loading. A finite element analysis (FEA) model was developed using the explicit dynamic nonlinear finite element code LS -DYNA in which the strain rate effects of both steel and concrete, contact between steel tube and concrete and confinement effect provided by the steel tube for the concrete were considered. The model also benefited from a relatively recent feature of LS-DYNA for applying a pre-loading in the explicit solver. The developed numerical model was verified for its accuracy and adequacy by comparing the results with experimental results available in the literature. The verified model was then employed to conduct a parametric study to investigate the influence of axial load level, impact location, support conditions, and slenderness ratio on the response of the CFST columns. A good agreement between the numerical and experimental results was achieved. The model could reasonably predict the impact load-deflection history and deformed shape of the column at the end of the impact event. The results of the parametric study showed that whilst impact location, axial load level and slenderness ratio can have a significant effect on the peak impact force, residual lateral deflection and maximum lateral deflection, the influence of support fixity is minimal. With an increase of axial load to up to a certain level, the peak force increases; however, a further increase in the axial load causes a decrease in the peak force. Both residual lateral deflection and maximum lateral deflection increase as axial load level increases. Shifting the impact location towards the supports increases the peak force and reduces both residual and maximum lateral deflections. A rise in slenderness ratio decreases the peak force and increases the residual and maximum lateral deflections.

Culture in global business transformation projects : the discovery of a grounded theory

Presently organisations engage in what is termed as Global Business Transformation Projects [GBTPs], for consolidating, innovating, transforming and restructuring their processes and business strategies while undergoing fundamental change. Culture plays an important role in global business transformation projects as these involve people of different cultural backgrounds and span across countries, industries and disciplinary boundaries. Nevertheless, there is scant empirical research on how culture is conceptualised beyond national and organisational cultures but also on how culture is to be taken into account and dealt with within global business transformation projects. This research is situated in a business context and discovers a theory that aids in describing and dealing with culture. It draws on the lived experiences of thirty-two senior management practitioners, reporting on more than sixty-one global business transformation projects in which they were actively involved. The research method used is a qualitative and interpretive one and applies a grounded theory approach, with rich data generated through interviews. In addition, vignettes were developed to illustrate the derived theoretical models. The findings from this study contribute to knowledge in multiple ways. First, it provides a holistic account of global business transformation projects that describe the construct of culture by the elements of culture types, cultural differences and cultural diversity. A typology of culture types has been developed which enlarges the view of culture beyond national and organisational culture including an industry culture, professional service firm culture and 'theme' culture. The amalgamation of the culture types instantiated in a global business transformation project compromises its project culture. Second, the empirically grounded process for managing culture in global business transformation projects integrates the stages of recognition, understanding and management as well as the enablement providing a roadmap for dealing with culture in global business transformation projects. Third, this study identified contextual variables to global business transformation projects, which provide the means of describing the environment global business transformation projects are situated, influence the construct of culture and inform the process for managing culture. Fourth, the contribution to the research method is the positioning of interview research as a strategy for data generation and the detailed documentation applying grounded theory to discover theory.

Open and networked initiatives and the digital transformation of academic publishing in China

Many aspects of China's academic publishing system differ from the systems found in liberal market based economies of the United States, Western Europe and Australia. A high level of government intervention in both the publishing industry and academia and the challenges associated with attempting to make a transition from a centrally controlled towards a more market based publishing industry are two notable differences; however, as in other countries, academic communities and publishers are being transformed by digital technologies. This research explores the complex yet dynamic digital transformation of academic publishing in China, with a specific focus of the open and networked initiatives inspired by Web 2.0 and social media. The thesis draws on two case studies: Science Paper Online, a government-operated online preprint platform and open access mandate; and New Science, a social reference management website operated by a group of young PhD students. Its analysis of the innovations, business models, operating strategies, influences, and difficulties faced by these two initiatives highlights important characteristics and trends in digital publishing experiments in China. The central argument of this thesis is that the open and collaborative possibilities of Web 2.0 inspired initiatives are emerging outside the established journal and monograph publishing system in China, introducing innovative and somewhat disruptive approaches to the certification, communication and commercial exploitation of knowledge. Moreover, emerging publishing models are enabling and encouraging a new system of practising and communicating science in China, putting into practice some elements of the Open Science ethos. There is evidence of both disruptive change to old publishing structures and the adaptive modification of emergent replacements in the Chinese practice. As such, the transformation from traditional to digital and interactive modes of publishing, involves both competition and convergence between new and old publishers, as well as dynamics of co-evolution involving new technologies, business models, social norms, and government reform agendas. One key concern driving this work is whether there are new opportunities and new models for academic publishing in the Web 2.0 age and social media environment, which might allow the basic functions of communication and certification to be achieved more effectively. This thesis enriches existing knowledge of open and networked transformations of scholarly publishing by adding a Chinese story. Although the development of open and networked publishing platforms in China remains in its infancy, the lessons provided by this research are relevant to practitioners and stakeholders interested in understanding the transformative dynamics of networked technologies for publishing and advocating open access in practice, not only in China, but also internationally.

New media and the transformation of higher education

One set of public institutions that has seen growing discussion about the transformative impact of new media technologies has been universities. The higher education sector, historically one of the more venerable and stable areas of public life, is now the subject of almost continuous speculation about whether it can continue in its current form during the 21st century. Digital media technologies are often seen as being at the forefront of such changes. It has been widely noted that moves towards a knowledge economy generates ‘skills-biased technological change’, that places a premium upon higher education qualifications, and that this earnings gap remains despite the continuing increase in the number of university graduates. As the demand for higher education continues to grow worldwide, there are new discussions about whether technologically-mediated education through new forms such as Massively Open Online Courses (MOOCs) are broadening access to quality learning, or severing the vital connection between teacher and student seen as integral to the learning process. This paper critically appraises such debates in the context of early 21st century higher education. It will discuss ten drivers of change in higher education, many of which are related to themes discussed elsewhere in this book, such as the impact of social media, globalization, and a knowledge economy. It will also consider the issues raised in navigating such developments from the perspective of the ‘Five P’s’: practical issues; personal issues; pedagogical issues; policy issues; and philosophical issues. It also includes a critical evaluation of MOOCs from the point of view of their educational qualities. It will conclude with the observation that while universities will continue to play a significant – and perhaps growing – role in the economy, society and culture, the issues raised about what Clayton Christensen and Henry Eyring term the ‘disruptive university’ (Christensen and Eyring 2011) are nonetheless pressing ones, and that cost and policy pressures in particular are likely to generate significant institutional transformations in higher education worldwide.

Storytelling beyond the anthropocene : a quest through the crises of ecocide toward new ecological paradigms

This project is a passionate and sometimes enraged thrust toward a biodiverse future. Weaving stories with deep thinking beyond the limits of the anthropocene, I am trying to recall myself in a more-than-human world. Our planet is suffering human induced ecocide which is a global crisis threatening the existence of multiple life forms. The alchemical mix of storytelling and ecological thinking could be part remedy for humanity's adaptation: a transformational mix to re-pattern the crisis into an opportunity and shift anthropocentric structures toward networks of dynamic relationships. The purpose of this project is to explore this cultural remedy. This is a quest, a search for tools that can germinate the hypothesis: storytelling in relation to ecological thinking manifests human potential in a more-than-human world. The practice-led research is guided by the philosophy and practice of Mythology, Deep ecology and Transdisciplinarity. Further navigation is sourced from Systems Thinking, Indigenous Methodologies, Biomimicry, and Quantum Physics. The journey unfolds by reawakening the Artist's function as caretaker of Mythology and pattern inciter for the collective. The resounding discovery of this adventure is Quantum Narratives: a storytelling tool for today's world, a method to connect multiple ways of knowing and diverse languages with the purpose of engaging, relating and working with living knowledge. Quantum Narratives are used to test the field study research into the Future of Water in context of Coal Seam Gas Mining in the Murray-Darling Basin and to materialise the collaborative results as the Water Stories. This thesis is a Living Script, full of imagination and complexity. Within its folds are strategies for systemic change ready to be adapted by policy and planning brokers and those who hold power for widespread remedial action.

Performance of a cognitive, but not visual, secondary task interacts with alcohol-induced balance impairment in novice and experienced motorcycle riders

The appropriateness of applying drink driving legislation to motorcycle riding has been questioned as there may be fundamental differences in the effects of alcohol on driving and motorcycling. It has been suggested that alcohol may redirect riders’ focus from higher-order cognitive skills such as cornering, judgement and hazard perception, to more physical skills such as maintaining balance. To test this hypothesis, the effects of low doses of alcohol on balance ability were investigated in a laboratory setting. The static balance of twenty experienced and twenty novice riders was measured while they performed either no secondary task, a visual (search) task, or a cognitive (arithmetic) task following the administration of alcohol (0%, 0.02%, and 0.05% BAC). Subjective ratings of intoxication and balance impairment increased in a dose-dependent manner in both novice and experienced motorcycle riders, while a BAC of 0.05%, but not 0.02%, was associated with impairments in static balance ability. This balance impairment was exacerbated when riders performed a cognitive, but not a visual, secondary task. Likewise, 0.05% BAC was associated with impairments in novice and experienced riders’ performance of a cognitive, but not a visual, secondary task, suggesting that interactive processes underlie balance and cognitive task performance. There were no observed differences between novice vs. experienced riders on static balance and secondary task performance, either alone or in combination. Implications for road safety and future ‘drink riding’ policy considerations are discussed.

Evaluating the dosimetric effect of treatment-induced changed in virally mediated head and neck cancer patients

Introduction Patients with virally mediated head and neck cancer (VMHNC) often present with advanced nodal disease that is highly radioresponsive as demonstrated by tumour and nodal regression during treatment. The resultant changes may impact on the planned dose distribution and so adversely affect the therapeutic ratio. The aim of this study was to evaluate the dosimetric effect of treatment-induced anatomical changes in VMHNC patients who had undergone a re-plan. Methods Thirteen patients with virally mediated oropharyngeal or nasopharyngeal cancer who presented for definitive radiotherapy between 2005 and 2010 and who had a re-plan generated were investigated. The dosimetric effect of anatomical changes, was quantified by comparing dose volume histograms (DVH) of primary and nodal gross target volumes and organs at risk (OAR), including spinal cord and parotid glands, from the original plan and a comparison plan. Results Eleven 3DCRT and 2 IMRT plans were evaluated. Dose to the spinal cord and brainstem increased by 4.1% and 2.6%, respectively. Mean dose to the parotid glands also increased by 3.5%. In contrast, the dose received by 98% of the primary and nodal gross tumour volumes decreased by 0.15% and 0.3%, respectively when comparing the initial treatment plan to the comparison plan. Conclusion In this study, treatment-induced anatomical changes had the greatest impact on OAR dose with negligible effect on the dose to nodal gross tumour volumes. In the era of intensity modulated radiotherapy (IMRT), accounting for treatment-induced anatomical changes is important as focus is placed on minimising the acute and long-term side effects of treatment.

Ultimate flexural limit states analysis of prestressed concrete sleeper

Railway is one of the most important, reliable and widely used means of transportation, carrying freight, passengers, minerals, grains, etc. Thus, research on railway tracks is extremely important for the development of railway engineering and technologies. The safe operation of a railway track is based on the railway track structure that includes rails, fasteners, pads, sleepers, ballast, subballast and formation. Sleepers are very important components of the entire structure and may be made of timber, concrete, steel or synthetic materials. Concrete sleepers were first installed around the middle of last century and currently are installed in great numbers around the world. Consequently, the design of concrete sleepers has a direct impact on the safe operation of railways. The "permissible stress" method is currently most commonly used to design sleepers. However, the permissible stress principle does not consider the ultimate strength of materials, probabilities of actual loads, and the risks associated with failure, all of which could lead to the conclusion of cost-ineffectiveness and over design of current prestressed concrete sleepers. Recently the limit states design method, which appeared in the last century and has been already applied in the design of buildings, bridges, etc, is proposed as a better method for the design of prestressed concrete sleepers. The limit states design has significant advantages compared to the permissible stress design, such as the utilisation of the full strength of the member, and a rational analysis of the probabilities related to sleeper strength and applied loads. This research aims to apply the ultimate limit states design to the prestressed concrete sleeper, namely to obtain the load factors of both static and dynamic loads for the ultimate limit states design equations. However, the sleepers in rail tracks require different safety levels for different types of tracks, which mean the different types of tracks have different load factors of limit states design equations. Therefore, the core tasks of this research are to find the load factors of the static component and dynamic component of loads on track and the strength reduction factor of the sleeper bending strength for the ultimate limit states design equations for four main types of tracks, i.e., heavy haul, freight, medium speed passenger and high speed passenger tracks. To find those factors, the multiple samples of static loads, dynamic loads and their distributions are needed. In the four types of tracks, the heavy haul track has the measured data from Braeside Line (A heavy haul line in Central Queensland), and the distributions of both static and dynamic loads can be found from these data. The other three types of tracks have no measured data from sites and the experimental data are hardly available. In order to generate the data samples and obtain their distributions, the computer based simulations were employed and assumed the wheel-track impacts as induced by different sizes of wheel flats. A valid simulation package named DTrack was firstly employed to generate the dynamic loads for the freight and medium speed passenger tracks. However, DTrack is only valid for the tracks which carry low or medium speed vehicles. Therefore, a 3-D finite element (FE) model was then established for the wheel-track impact analysis of the high speed track. This FE model has been validated by comparing its simulation results with the DTrack simulation results, and with the results from traditional theoretical calculations based on the case of heavy haul track. Furthermore, the dynamic load data of the high speed track were obtained from the FE model and the distributions of both static and dynamic loads were extracted accordingly. All derived distributions of loads were fitted by appropriate functions. Through extrapolating those distributions, the important parameters of distributions for the static load induced sleeper bending moment and the extreme wheel-rail impact force induced sleeper dynamic bending moments and finally, the load factors, were obtained. Eventually, the load factors were obtained by the limit states design calibration based on reliability analyses with the derived distributions. After that, a sensitivity analysis was performed and the reliability of the achieved limit states design equations was confirmed. It has been found that the limit states design can be effectively applied to railway concrete sleepers. This research significantly contributes to railway engineering and the track safety area. It helps to decrease the failure and risks of track structure and accidents; better determines the load range for existing sleepers in track; better rates the strength of concrete sleepers to support bigger impact and loads on railway track; increases the reliability of the concrete sleepers and hugely saves investments on railway industries. Based on this research, many other bodies of research can be promoted in the future. Firstly, it has been found that the 3-D FE model is suitable for the study of track loadings and track structure vibrations. Secondly, the equations for serviceability and damageability limit states can be developed based on the concepts of limit states design equations of concrete sleepers obtained in this research, which are for the ultimate limit states.

Real - time prediction of rainfall induced instability of residual soil slopes associated with deep cracks

The early warning based on real-time prediction of rain-induced instability of natural residual slopes helps to minimise human casualties due to such slope failures. Slope instability prediction is complicated, as it is influenced by many factors, including soil properties, soil behaviour, slope geometry, and the location and size of deep cracks in the slope. These deep cracks can facilitate rainwater infiltration into the deep soil layers and reduce the unsaturated shear strength of residual soil. Subsequently, it can form a slip surface, triggering a landslide even in partially saturated soil slopes. Although past research has shown the effects of surface-cracks on soil stability, research examining the influence of deep-cracks on soil stability is very limited. This study aimed to develop methodologies for predicting the real-time rain-induced instability of natural residual soil slopes with deep cracks. The results can be used to warn against potential rain-induced slope failures. The literature review conducted on rain induced slope instability of unsaturated residual soil associated with soil crack, reveals that only limited studies have been done in the following areas related to this topic: - Methods for detecting deep cracks in residual soil slopes. - Practical application of unsaturated soil theory in slope stability analysis. - Mechanistic methods for real-time prediction of rain induced residual soil slope instability in critical slopes with deep cracks. Two natural residual soil slopes at Jombok Village, Ngantang City, Indonesia, which are located near a residential area, were investigated to obtain the parameters required for the stability analysis of the slope. A survey first identified all related field geometrical information including slope, roads, rivers, buildings, and boundaries of the slope. Second, the electrical resistivity tomography (ERT) method was used on the slope to identify the location and geometrical characteristics of deep cracks. The two ERT array models employed in this research are: Dipole-dipole and Azimuthal. Next, bore-hole tests were conducted at different locations in the slope to identify soil layers and to collect undisturbed soil samples for laboratory measurement of the soil parameters required for the stability analysis. At the same bore hole locations, Standard Penetration Test (SPT) was undertaken. Undisturbed soil samples taken from the bore-holes were tested in a laboratory to determine the variation of the following soil properties with the depth: - Classification and physical properties such as grain size distribution, atterberg limits, water content, dry density and specific gravity. - Saturated and unsaturated shear strength properties using direct shear apparatus. - Soil water characteristic curves (SWCC) using filter paper method. - Saturated hydraulic conductivity. The following three methods were used to detect and simulate the location and orientation of cracks in the investigated slope: (1) The electrical resistivity distribution of sub-soil obtained from ERT. (2) The profile of classification and physical properties of the soil, based on laboratory testing of soil samples collected from bore-holes and visual observations of the cracks on the slope surface. (3) The results of stress distribution obtained from 2D dynamic analysis of the slope using QUAKE/W software, together with the laboratory measured soil parameters and earthquake records of the area. It was assumed that the deep crack in the slope under investigation was generated by earthquakes. A good agreement was obtained when comparing the location and the orientation of the cracks detected by Method-1 and Method-2. However, the simulated cracks in Method-3 were not in good agreement with the output of Method-1 and Method-2. This may have been due to the material properties used and the assumptions made, for the analysis. From Method-1 and Method-2, it can be concluded that the ERT method can be used to detect the location and orientation of a crack in a soil slope, when the ERT is conducted in very dry or very wet soil conditions. In this study, the cracks detected by the ERT were used for stability analysis of the slope. The stability of the slope was determined using the factor of safety (FOS) of a critical slip surface obtained by SLOPE/W using the limit equilibrium method. Pore-water pressure values for the stability analysis were obtained by coupling the transient seepage analysis of the slope using finite element based software, called SEEP/W. A parametric study conducted on the stability of an investigated slope revealed that the existence of deep cracks and their location in the soil slope are critical for its stability. The following two steps are proposed to predict the rain-induced instability of a residual soil slope with cracks. (a) Step-1: The transient stability analysis of the slope is conducted from the date of the investigation (initial conditions are based on the investigation) to the preferred date (current date), using measured rainfall data. Then, the stability analyses are continued for the next 12 months using the predicted annual rainfall that will be based on the previous five years rainfall data for the area. (b) Step-2: The stability of the slope is calculated in real-time using real-time measured rainfall. In this calculation, rainfall is predicted for the next hour or 24 hours and the stability of the slope is calculated one hour or 24 hours in advance using real time rainfall data. If Step-1 analysis shows critical stability for the forthcoming year, it is recommended that Step-2 be used for more accurate warning against the future failure of the slope. In this research, the results of the application of the Step-1 on an investigated slope (Slope-1) showed that its stability was not approaching a critical value for year 2012 (until 31st December 2012) and therefore, the application of Step-2 was not necessary for the year 2012. A case study (Slope-2) was used to verify the applicability of the complete proposed predictive method. A landslide event at Slope-2 occurred on 31st October 2010. The transient seepage and stability analyses of the slope using data obtained from field tests such as Bore-hole, SPT, ERT and Laboratory tests, were conducted on 12th June 2010 following the Step-1 and found that the slope in critical condition on that current date. It was then showing that the application of the Step-2 could have predicted this failure by giving sufficient warning time.

Osteogenic differentiation of bone marrow MSCs by β-tricalcium phosphate stimulating macrophages via BMP2 signalling pathway

Immune reactions play important roles in determining the in vivo fate of bone substitute materials, either in new bone formation or inflammatory fibrous tissue encapsulation. The paradigm for the development of bone substitute materials has been shifted from inert to immunomodulatory materials, emphasizing the importance of immune cells in the material evaluation. Macrophages, the major effector cells in the immune reaction to implants, are indispensable for osteogenesis and their heterogeneity and plasticity render macrophages a primer target for immune system modulation. However, there are very few reports about the effects of macrophages on biomaterial-regulated osteogenesis. In this study, we used b-tricalcium phosphate (b-TCP) as a model biomaterial to investigate the role of macrophages on the material stimulated osteogenesis. The macrophage phenotype switched to M2 extreme in response to b-TCP extracts, which was related to the activation of calcium-sensing receptor (CaSR) pathway. Bone morphogenetic protein 2 (BMP2) was also significantly upregulated by the b-TCP stimulation, indicating that macrophage may participate in the b-TCP stimulated osteogenesis. Interestingly, when macrophageconditioned b-TCP extracts were applied to bone marrow mesenchymal stem cells (BMSCs), the osteogenic differentiation of BMSCs was significantly enhanced, indicating the important role of macrophages in biomaterial-induced osteogenesis. These findings provided valuable insights into the mechanism of material-stimulated osteogenesis, and a strategy to optimize the evaluation system for the in vitro osteogenesis capacity of bone substitute materials.

Osteocyte-induced angiogenesis via VEGF–MAPK-dependent pathways in endothelial cells

Recently, it has been suggested osteocytes control the activities of bone formation (osteoblasts) and resorption (osteoclast), indicating their important regulatory role in bone remodelling. However, to date, the role of osteocytes in controlling bone vascularisation remains unknown. Our aim was to investigate the interaction between endothelial cells and osteocytes and to explore the possible molecular mechanisms during angiogenesis. To model osteocyte/endothelial cell interactions, we co-cultured osteocyte cell line (MLOY4) with endothelial cell line (HUVECs). Co-cultures were performed in 1:1 mixture of osteocytes and endothelial cells or by using the conditioned media (CM) transfer method. Real-time cell migration of HUVECs was measured with the transwell migration assay and xCELLigence system. Expression levels of angiogenesis- related genes were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The effect of vascular endothelial growth factor (VEGF) and mitogen-activated phosphorylated kinase (MAPK) signaling were monitored by western blotting using relevant antibodies and inhibitors. During the bone formation, it was noted that osteocyte dendritic processes were closely connected to the blood vessels. The CM generated from MLOY4 cells-activated proliferation, migration, tube-like structure formation, and upregulation of angiogenic genes in endothelial cells suggesting that secretory factor(s) from osteocytes could be responsible for angiogenesis. Furthermore, we identified that VEGF secreted from MLOY4-activated VEGFR2–MAPK–ERK-signaling pathways in HUVECs. Inhibiting VEGF and/or MAPK–ERK pathways abrogated osteocyte-mediated angiogenesis in HUVEC cells. Our data suggest an important role of osteocytes in regulating angiogenesis.

Contraction-induced changes in TNFα and Akt-mediated signalling are associated with increased myofibrillar protein in rat skeletal muscle

Resistance training results in skeletal muscle hypertrophy, but the molecular signalling mechanisms responsible for this altered phenotype are incompletely understood. We used a resistance training (RT) protocol consisting of three sessions [day 1 (d1), day 3 (d3), day 5 (d5)] separated by 48 h recovery (squat exercise, 4 sets × 10 repetitions, 3 min recovery) to determine early signalling responses to RT in rodent skeletal muscle. Six animals per group were killed 3 h after each resistance training session and 24 and 48 h after the last training session (d5). There was a robust increase in TNF? protein expression, and IKKSer180/181 and p38MAPK Thr180/Tyr182 phosphorylation on d1 (P < 0.05), which abated with subsequent RT, returning to control levels by d5 for TNF? and IKK Ser180/181. There was a trend for a decrease in MuRF-1 protein expression, 48 h following d5 of training (P = 0.08). Notably, muscle myofibrillar protein concentration was elevated compared to control 24 and 48 h following RT (P < 0.05). AktSer473 and mTORSer2448 phosphorylation were unchanged throughout RT. Phosphorylation of p70S6k Thr389 increased 3 h post-exercise on d1, d3 and d5 (P < 0.05), whilst phosphorylation of S6Ser235/236 increased on d1 and d3 (P < 0.05). Our results show a rapid attenuation of inflammatory signalling with repeated bouts of resistance exercise, concomitant with summation in translation initiation signalling in skeletal muscle. Indeed, the cumulative effect of these signalling events was associated with myofibrillar protein accretion, which likely contributes to the early adaptations in response to resistance training overload in the skeletal muscle.

The molecular bases of training adaptation

Skeletal muscle is a malleable tissue capable of altering the type and amount of protein in response to disruptions to cellular homeostasis. The process of exercise-induced adaptation in skeletal muscle involves a multitude of signalling mechanisms initiating replication of specific DNA genetic sequences, enabling subsequent translation of the genetic message and ultimately generating a series of amino acids that form new proteins. The functional consequences of these adaptations are determined by training volume, intensity and frequency, and the half-life of the protein. Moreover, many features of the training adaptation are specific to the type of stimulus, such as the mode of exercise. Prolonged endurance training elicits a variety of metabolic and morphological changes, including mitochondrial biogenesis, fast-to-slow fibre-type transformation and substrate metabolism. In contrast, heavy resistance exercise stimulates synthesis of contractile proteins responsible for muscle hypertrophy and increases in maximal contractile force output. Concomitant with the vastly different functional outcomes induced by these diverse exercise modes, the genetic and molecular mechanisms of adaptation are distinct. With recent advances in technology, it is now possible to study the effects of various training interventions on a variety of signalling proteins and early-response genes in skeletal muscle. Although it cannot presently be claimed that such scientific endeavours have influenced the training practices of elite athletes, these new and exciting technologies have provided insight into how current training techniques result in specific muscular adaptations, and may ultimately provide clues for future and novel training methodologies. Greater knowledge of the mechanisms and interaction of exercise-induced adaptive pathways in skeletal muscle is important for our understanding of the aetiology of disease, maintenance of metabolic and functional capacity with aging, and training for athletic performance. This article highlights the effects of exercise on molecular and genetic mechanisms of training adaptation in skeletal muscle.