Role of insulin-like growth factor binding protein-4 in prevention of colon cancer

Insulin-like growth factors (IGFs) are important for the proliferation of cancer cells. One of their binding proteins, known as insulin-like growth factor binding protein -4 (IGFBP-4) is well known for its inhibitory action on IGFs in vitro. We assessed the effect of IGFBP-4 in prevention of development of colon cancer in vivo

The adult heart responds to increased workload with physiologic hypertrophy, cardiac stem cell activation, and new myocyte formation

Aims It is a dogma of cardiovascular pathophysiology that the increased cardiac mass in response to increased workload is produced by the hypertrophy of the pre-existing myocytes. The role, if any, of adult-resident endogenous cardiac stem/progenitor cells (eCSCs) and new cardiomyocyte formation in physiological cardiac remodelling remains unexplored. Methods and results In response to regular, intensity-controlled exercise training, adult rats respond with hypertrophy of the pre-existing myocytes. In addition, a significant number (∼7%) of smaller newly formed BrdU-positive cardiomyocytes are produced by the exercised animals. Capillary density significantly increased in exercised animals, balancing cardiomyogenesis with neo-angiogenesis. c-kitpos eCSCs increased their number and activated state in exercising vs. sedentary animals. c-kitpos eCSCs in exercised hearts showed an increased expression of transcription factors, indicative of their commitment to either the cardiomyocyte (Nkx2.5pos) or capillary (Ets-1pos) lineages. These adaptations were dependent on exercise duration and intensity. Insulin-like growth factor-1, transforming growth factor-β1, neuregulin-1, bone morphogenetic protein-10, and periostin were significantly up-regulated in cardiomyocytes of exercised vs. sedentary animals. These factors differentially stimulated c-kitpos eCSC proliferation and commitment in vitro, pointing to a similar role in vivo. Conclusion Intensity-controlled exercise training initiates myocardial remodelling through increased cardiomyocyte growth factor expression leading to cardiomyocyte hypertrophy and to activation and ensuing differentiation of c-kitpos eCSCs. This leads to the generation of new myocardial cells. These findings highlight the endogenous regenerative capacity of the adult heart, represented by the eCSCs, and the fact that the physiological cardiac adaptation to exercise stress is a combination of cardiomyocyte hypertrophy and hyperplasia (cardiomyocytes and capillaries)

Combination of optison with ultrasound and electroporation increases albumin and thrompoietin transgene expression whilst elongation factor promoter prolongs its duration

Hypoalbuminaemia and thrombocytopaenia are two clinical problems frequently encountered in patients with chronic liver failure or cancer following treatment with chemotherapy. The current study was designed to assess the magnitude and duration of thrombopoietin and albumin transgene expression hoping to increase the production of albumin and platelets. Immunocompetent and immunocompromised (nude) mice were injected intramuscularly with plasmids expressing either human serum albumin or human thrombopoietin. The therapeutic expression cassette of the plasmids was driven by either CMV or elongation factor 1- promoters respectively. In order to achieve muscle specific expression both gene constructs included the myosin light chain enhancer. The experiment was conducted in a group of mice which were injected with the transgene plasmid either in normal saline or plasmid followed by electroporation, ultrasound, optison and a combination of all three to increase transgene expression. The result showed that plasmids with the CMV promoter induced the highest transgenic expression lasting for one week whilst plasmids with the elongation factor 1-alpha promoter produced a weaker expression lasting for a longer and more stable duration of expression up to 3 months in both immunocompetent and nude mice. The combination of electroporation and ultrasound with Optison TM provided the highest transgene expression. We concluded that it would be possible to increase albumin and platelets production by an intramuscular injection of plasmids expressing human albumin and thromopoietin. A combination of electroporation and ultrasound with Optison TM can increase their expression

The FuturICT education accelerator

Education is a major force for economic and social wellbeing. Despite high aspirations, education at all levels can be expensive and ineffective. Three Grand Challenges are identified: (1) enable people to learn orders of magnitude more effectively, (2) enable people to learn at orders of magnitude less cost, and (3) demonstrate success by exemplary interdisciplinary education in complex systems science. A ten year ‘man-on-the-moon’ project is proposed in which FuturICT’s unique combination of Complexity, Social and Computing Sciences could provide an urgently needed transdisciplinary language for making sense of educational systems. In close dialogue with educational theory and practice, and grounded in the emerging data science and learning analytics paradigms, this will translate into practical tools (both analytical and computational) for researchers, practitioners and leaders; generative principles for resilient educational ecosystems; and innovation for radically scalable, yet personalised, learner engagement and assessment. The proposed Education Accelerator will serve as a ‘wind tunnel’ for testing these ideas in the context of real educational programmes, with an international virtual campus delivering complex systems education exploiting the new understanding of complex, social, computationally enhanced organisational structure developed within FuturICT

The FuturICT education accelerator

Education is a major force for economic and social wellbeing. Despite high aspirations, education at all levels can be expensive and ineffective. Three Grand Challenges are identified: (1) enable people to learn orders of magnitude more effectively, (2) enable people to learn at orders of magnitude less cost, and (3) demonstrate success by exemplary interdisciplinary education in complex systems science. A ten year ‘man-on-the-moon’ project is proposed in which FuturICT’s unique combination of Complexity, Social and Computing Sciences could provide an urgently needed transdisciplinary language for making sense of educational systems. In close dialogue with educational theory and practice, and grounded in the emerging data science and learning analytics paradigms, this will translate into practical tools (both analytical and computational) for researchers, practitioners and leaders; generative principles for resilient educational ecosystems; and innovation for radically scalable, yet personalised, learner engagement and assessment. The proposed Education Accelerator will serve as a ‘wind tunnel’ for testing these ideas in the context of real educational programmes, with an international virtual campus delivering complex systems education exploiting the new understanding of complex, social, computationally enhanced organisational structure developed within FuturICT

Local Government's effective community responses

Speech given at the conference 'Reducing criminality: partnerships and best practice', Perth, 31 July to 1 August 2000, by Adam Graycar, Director, Australian Institute of Criminology. This speech is made available under the CC-BY-NC-ND 4.0 license: http://creativecommons.org/licenses/by-nc-nd/4.0/The challenge before us is to find the right set of interventions to prevent criminal behaviour among young people, and prevent that behaviour becoming a lifelong activity. The two main strategies are on the one hand to reduce the supply of motivated offenders, and on the other to make crime more difficult to commit. Crime is the result of complex changes in economic, social and cultural factors such as unemployment, dysfunctional families, child abuse, poor education, community breakdown, economic inequality and substance abuse. If crime prevention is to succeed it should focus on broad social outcomes, for example reducing social exclusion. Compelling evidence suggests that those who feel excluded from participation in community life are more likely to offend against that community. Addressing this sense of exclusion can reduce the risk of offending. In simple terms the criminal justice domain plays only a small part in crime prevention and preventing the supply of motivated offenders

Hypertrophy of mature xenopus muscle fibres in culture induced by synergy of albumin and insulin

The aim of this study was to investigate effects of albumin and insulin separately as well as in combination on mature muscle fibres during long-term culture. Single muscle fibres were dissected from m. iliofibularis of Xenopus laevis and attached to a force transducer in a culture chamber. Fibres were cultured in a serum-free medium at slack length (mean sarcomere length 2.3 μm) for 8 to 22 days. The medium was supplemented with (final concentrations): (1) bovine insulin (6 nmol/L or 200-600 nmol/L), (2) 0.2% bovine albumin or (3) 0.2% bovine albumin in combination with insulin (120 nmol/L). In culture medium with insulin, 50% of the muscle fibres became in-excitable within 7-12 days, whereas the other 50% were stable. Caffeine contractures of in-excitable muscle fibres produced 80.4±2.4% of initial peak tetanic force, indicating impaired excitation-contraction (E-C) coupling in in-excitable fibres. In the presence of albumin, all cultured muscle fibres were stable for at least 10 days. Muscle fibres cultured in medium with insulin or albumin exclusively did not hypertrophy or change the number of sarcomeres in series. In contrast, muscle fibres cultured with both albumin and insulin showed an increase in tetanic force and fibre cross-sectional area of 19.6±2.8% and 32.5±4.9%, respectively, (means±SEM.; P=0.007) after 16.3±1.7 days, whereas the number of sarcomeres in series remained unchanged. We conclude that albumin prevents muscle fibre damage and preserves E-C coupling in culture. Furthermore, albumin is important in regulating muscle fibre adaptation by a synergistic action with growth factors like insulin. © 2008 The Author(s)

Dystropathology increases energy expenditure and protein turnover in the mdx mouse model of Duchenne muscular dystrophy

The skeletal muscles in Duchenne muscular dystrophy and the mdx mouse model lack functional dystrophin and undergo repeated bouts of necrosis, regeneration, and growth. These processes have a high metabolic cost. However, the consequences for whole body energy and protein metabolism, and on the dietary requirements for these macronutrients at different stages of the disease, are not well-understood. This study used juvenile (4- to 5- wk-old) and adult (12- to 14-wk-old) male dystrophic C57BL/10ScSn-mdx/J and age-matched C57BL/10ScSn/J control male mice to measure total and resting energy expenditure, food intake, spontaneous activity, body composition, whole body protein turnover, and muscle protein synthesis rates. In juvenile mdx mice that have extensive muscle damage, energy expenditure, muscle protein synthesis, and whole body protein turnover rates were higher than in age-matched controls. Adaptations in food intake and decreased activity were insufficient to meet the increased energy and protein needs of juvenile mdx mice and resulted in stunted growth. In (non-growing) adult mdx mice with less severe dystropathology, energy expenditure, muscle protein synthesis, and whole body protein turnover rates were also higher than in age-matched controls. Food intake was sufficient to meet their protein and energy needs, but insufficient to result in fat deposition. These data show that dystropathology impacts the protein and energy needs of mdx mice and that tailored dietary interventions are necessary to redress this imbalance. If not met, the resultant imbalance blunts growth, and may limit the benefits of therapies designed to protect and repair dystrophic muscles