Intrauterine growth restriction due to uteroplacental vascular insufficiency leads to increased hypoxia-induced cerebral apoptosis in newborn piglets

Uteroplacental vascular insufficiency in humans is a common cause of intrauterine growth restriction (IUGR) and is associated with an increased incidence of perinatal asphyxia and neurodevelopmental disorders compared to normal weight newborns. Experimental models that provide an opportunity to analyze the pathogenesis of these relationships are limited. Here, we used neonatal pigs from large litters in which there were piglets of normal birth weight (for controls) and of low birth weight (for uteroplacental vascular insufficiency). Hypoxia was induced in paired littermates by reducing the fraction of inspired oxygen to 4% for 25 min. Brain tissue was collected 4 h post-hypoxia. Cerebral levels of apoptosis were quantified morphologically and verified with caspase-3 activity and TUNEL. Expression of Bcl-2, BcI-XL and Bax proteins was investigated using immunohistochemistry. Cellular positivity for Bcl-2 was consistently higher in the non-apoptotic white matter of the hypoxic IUGR animals compared with their littermates and reached significance at P < 0.05 in several pairs of littermates. Alterations in Bax showed a trend towards higher expression in the hypoxic IUGR littermates but rarely reached significance. The IUGR piglets showed a significantly greater amount of apoptosis in response to the hypoxia than the normal weight piglets, suggesting an increased vulnerability to apoptosis in the IUGR piglets. (c) 2006 Elsevier B.V. All rights reserved.

Effects of high temperature on the growth and composition of sugarcane internodes

Sugarcane grown in the Ord River district of Western Australia has lower sucrose content than expected from earlier trials and experience in other irrigated districts. High temperatures have been hypothesised as a possible cause. The effects of high temperature (above 32 degrees C) on growth and carbon partitioning were investigated. A temperature regime of (25-38 degrees C) was compared with (23-33 degrees C). In one experiment, 7-month-old plants of cvv. Q117 and Q158 were subjected to the treatments for 2 months. In another experiment, the plants were allowed to regrow (ratoon) for 6 months. In both experiments, the higher temperature resulted in more, shorter internodes and higher moisture content. Most internodes from plants in the higher temperature treatment had lower sucrose content than internodes from the lower temperature. On a dry mass basis the internodes from the plants in the higher temperature had proportionately more fibre and hexoses but lower sucrose. Combined with an increased number of nodes in a stem of similar or shorter length this would result in higher stalk fibre and lower sucrose content. The data provided evidence that sugarcane partitions less carbon to stored sucrose when grown under high compared with low temperatures. The two cultivars partitioned carbon between soluble (sugars) and insoluble (fibre) fractions to different degrees. These experiments also indicate that the current models describing leaf appearance and perhaps sugarcane growth at temperatures above 32 degrees C, in general, need revision.

Physical activity and strength of the femoral neck during the adolescent growth spurt: A longitudinal analysis

Loading of the femoral neck (FN) is dominated by bending and compressive stresses. We hypothesize that adaptation of the FN to physical activity would be manifested in the cross-sectional area (CSA) and section modulus (Z) of bone, indices of axial and bending strength, respectively. We investigated the influence of physical activity on bone strength during adolescence using 7 years of longitudinal data from 109 boys and 121 girls from the Saskatchewan Paediatric Bone and Mineral Accrual Study (PBMAS). Physical activity data (PAC-Q physical activity inventory) and anthropometric measurements were taken every 6 months and DXA bone scans were measured annually (Hologic QDR2000, array mode). We applied hip structural analysis to derive strength and geometric indices of the femoral neck using DXA scans. To control for maturation, we determined a biological maturity age defined as years from age at peak height velocity (APHV). To account for the repeated measures within individual nature of longitudinal data, multilevel random effects regression analyses were used to analyze the data. When biological maturity age and body size (height and weight) were controlled, in both boys and girls, physical activity was a significant positive independent predictor of CSA and Z of the narrow region of the femoral neck (P < 0.05). There was no independent effect of physical activity on the subperiosteal width of the femoral neck. When leg length and leg lean mass were introduced into the random effects models to control for size and muscle mass of the leg (instead of height and weight), all significant effects of physical activity disappeared. Even among adolescents engaged in normal levels of physical activity, the statistically significant relationship between physical activity and indices of bone strength demonstrate that modifiable lifestyle factors like exercise play an important role in optimizing bone strength during the growing years. Physical activity differences were explained by the interdependence between activity and lean mass considerations. Physical activity is important for optimal development of bone strength. (c) 2005 Elsevier Inc. All rights reserved.

Characterization of the transcriptional and functional effects of fibroblast growth factor-1 on human preadipocyte differentiation

We recently established that fibroblast growth factor (FGF)-1 promotes adipogenesis of primary human preadipocytes (phPA). In the current report, we have characterized the adipogenic effects of FGF-1 in phPA and also in a human PA strain derived from an individual with Simpson-Golabi-Behmel syndrome (SGBS PA), which exhibit an intrinsic capacity to differentiate with high efficiency. In further studies, we compared these models with the well-characterized murine 3T3-L1 preadipocyte cell line (3T3-L1 PA). FGF-1 up-regulated the adipogenic program in phPA, with increased expression of peroxisome proliferator-activated receptor-gamma in confluent PA prior to induction of differentiation and increased expression of adipocyte markers during differentiation. Moreover, phPA differentiated in the presence of FGF-1 were more insulin responsive and secreted increased levels of adiponectin. FGF-1 treatment of SGBS PA further enhanced differentiation. For the most part, the adipogenic program in phPA paralleled that observed in 3T3-L1 PA; however, we found no evidence of mitotic clonal expansion in the phPA. Finally, we investigated a role for extracellular regulated kinase 1/2 (ERK 1/2) in adipogenesis of phPA. FGF-1 induced robust phosphorylation of ERK1/2 in early differentiation and inhibition of ERK1/2 activity significantly reduced phPA differentiation. These data suggest that FGF-1 treated phPA represent a valuable in vitro model for the study of adipogenesis and insulin action and indicate that ERK1/2 activation is necessary for human adipogenesis in the absence of mitotic clonal expansion.

Accounting for management costs in sensitivity analyses of matrix population models

Traditional sensitivity and elasticity analyses of matrix population models have been used to p inform management decisions, but they ignore the economic costs of manipulating vital rates. For exam le, the growth rate of a population is often most sensitive to changes in adult survival rate, but this does not mean that increasing that rate is the best option for managing the population because it may be much more expensive than other options. To explore how managers should optimize their manipulation of vital rates, we incorporated the cost of changing those rates into matrix population models. We derived analytic expressions for locations in parameter space where managers should shift between management of fecundity and survival, for the balance between fecundity and survival management at those boundaries, and for the allocation of management resources to sustain that optimal balance. For simple matrices, the optimal budget allocation can often be expressed as simple functions of vital rates and the relative costs of changing them. We applied our method to management of the Helmeted Honeyeater (Lichenostomus melanops cassidix; an endangered Australian bird) and the koala (Phascolarctos cinereus) as examples. Our method showed that cost-efficient management of the Helmeted Honeyeater should focus on increasing fecundity via nest protection, whereas optimal koala management should focus on manipulating both fecundity and survival simultaneously, These findings are contrary to the cost-negligent recommendations of elasticity analysis, which would suggest focusing on managing survival in both cases. A further investigation of Helmeted Honeyeater management options, based on an individual-based model incorporating density dependence, spatial structure, and environmental stochasticity, confirmed that fecundity management was the most cost-effective strategy. Our results demonstrate that decisions that ignore economic factors will reduce management efficiency.

Towards developing reliable models of leaf area on grapevines (Vitis vinifera L.)

A field study in three vineyards in southern Queensland (Australia) was carried out to develop predictive models for individual leaf area and shoot leaf area of two cultivars (Cabernet Sauvignon and Shiraz) of grapevines (Vitis Vinifera L.). Digital image analysis was used to measure leaf vein length and leaf area. Stepwise regressions of untransformed and transformed models consisting of up to six predictor variables for leaf area and three predictor variables for shoot leaf area were carried out to obtain the most efficient models. High correlation coefficients were found for log10 transformed individual leaf and shoot leaf area models. The significance of predictor variables in the models varied across vineyards and cultivars, demonstrating the discontinuous and heterogeneous nature of vineyards. The application of this work in a grapevine modeling environment and in a dynamic vineyard management context are discussed. Sample sizes for quantification of individual leaf areas and areas of leaves on shoots are proposed based on target margins of errors of sampled data.

Modelling the growth of prion protein aggregates in the brain in variant Creutzfeldt-Jakob disease

Deposition of insoluble prion protein (PrP) in the brain in the form of protein aggregates or deposits is characteristic of the ‘transmissible spongiform encephalopathies’ (TSEs). Understanding the growth and development of these PrP aggregates is important both in attempting to the elucidate of the pathogenesis of prion disease and in the development of treatments designed to prevent or inhibit the spread of prion pathology within the brain. Aggregation and disaggregation of proteins and the diffusion of substances into the developing aggregates (surface diffusion) are important factors in the development of protein aggregates. Mathematical models suggest that if aggregation/disaggregation or surface diffusion is the predominant factor, the size frequency distribution of the resulting protein aggregates in the brain should be described by either a power-law or a log-normal model respectively. This study tested this hypothesis for two different types of PrP deposit, viz., the diffuse and florid-type PrP deposits in patients with variant Creutzfeldt-Jakob disease (vCJD). The size distributions of the florid and diffuse plaques were fitted by a power-law function in 100% and 42% of brain areas studied respectively. By contrast, the size distributions of both types of plaque deviated significantly from a log-normal model in all brain areas. Hence, protein aggregation and disaggregation may be the predominant factor in the development of the florid plaques. A more complex combination of factors appears to be involved in the pathogenesis of the diffuse plaques. These results may be useful in the design of treatments to inhibit the development of protein aggregates in vCJD.

The impact of procurement-driven technological change on U.S. manufacturing productivity growth

As we enter the 21st Century, technologies originally developed for defense purposes such as computers and satellite communications appear to have become a driving force behind economic growth in the United States. Paradoxically, almost all previous econometric models suggest that the largely defense-oriented federal industrial R&D funding that helped create these technologies had no discernible effect on U.S. industrial productivity growth. This paper addresses this paradox by stressing that defense procurement as well as federal R&D expenditures were targeted to a few narrowly defined manufacturing sub-sectors that produced high tech weaponry. Analysis employing data from the NBER Manufacturing Productivity Database and the BEA' s Input Output tables then demonstrates that defense procurement policies did have significant effects on the productivity performance of disaggregated manufacturing industries because of a process of procurement-driven technological change.

Three-factor models versus time series models:quantifying time-dependencies of interactions between stimuli in cell biology and psychobiology for short longitudinal data

Signal integration determines cell fate on the cellular level, affects cognitive processes and affective responses on the behavioural level, and is likely to be involved in psychoneurobiological processes underlying mood disorders. Interactions between stimuli may subjected to time effects. Time-dependencies of interactions between stimuli typically lead to complex cell responses and complex responses on the behavioural level. We show that both three-factor models and time series models can be used to uncover such time-dependencies. However, we argue that for short longitudinal data the three factor modelling approach is more suitable. In order to illustrate both approaches, we re-analysed previously published short longitudinal data sets. We found that in human embryonic kidney 293 cells cells the interaction effect in the regulation of extracellular signal-regulated kinase (ERK) 1 signalling activation by insulin and epidermal growth factor is subjected to a time effect and dramatically decays at peak values of ERK activation. In contrast, we found that the interaction effect induced by hypoxia and tumour necrosis factor-alpha for the transcriptional activity of the human cyclo-oxygenase-2 promoter in HEK293 cells is time invariant at least in the first 12-h time window after stimulation. Furthermore, we applied the three-factor model to previously reported animal studies. In these studies, memory storage was found to be subjected to an interaction effect of the beta-adrenoceptor agonist clenbuterol and certain antagonists acting on the alpha-1-adrenoceptor / glucocorticoid-receptor system. Our model-based analysis suggests that only if the antagonist drug is administer in a critical time window, then the interaction effect is relevant.

What does endogenous growth theory tell about regional economies? Empirics of R&D worker-based productivity growth

What does endogenous growth theory tell about regional economies? Empirics of R&D worker-based productivity growth, Regional Studies. Endogenous growth theory emerged in the 1990s as ‘new growth theory’ accounting for technical progress in the growth process. This paper examines the role of research and development (R&D) workers underlying the Romer model (1990) and its subsequent modifications, and compares it with a model based on the accumulation of human capital engaged in R&D. Cross-section estimates of the models against productivity growth of European regions in the 1990s suggest that each R&D worker has a unique set of knowledge while his/her contributions are enhanced by knowledge sharing within a region as well as spillovers from other regions in proximity.

Modelling growth of prion protein aggregates in the brain in variant Creutzfeldt-Jakob disease

Deposition of insoluble prion protein (PrP) in the brain in the form of protein aggregates or deposits is characteristic of the ‘transmissible spongiform encephalopathies’ (TSEs). Understanding the growth and development of PrP aggregates is important both in attempting to elucidate the pathogenesis of prion disease and in the development of treatments designed to inhibit the spread of prion pathology within the brain. Aggregation and disaggregation of proteins and the diffusion of substances into the developing aggregates (surface diffusion) are important factors in the development of protein deposits. Mathematical models suggest that if either aggregation/disaggregation or surface diffusion is the predominant factor, then the size frequency distribution of the resulting protein aggregates will be described by either a power-law or a log-normal model respectively. This study tested this hypothesis for two different populations of PrP deposit, viz., the diffuse and florid-type PrP deposits characteristic of patients with variant Creutzfeldt-Jakob disease (vCJD). The size distributions of the florid and diffuse deposits were fitted by a power-law function in 100% and 42% of brain areas studied respectively. By contrast, the size distributions of both types of aggregate deviated significantly from a log-normal model in all areas. Hence, protein aggregation and disaggregation may be the predominant factor in the development of the florid deposits. A more complex combination of factors appears to be involved in the pathogenesis of the diffuse deposits. These results may be useful in the design of treatments to inhibit the development of PrP aggregates in vCJD.

Increasing cell biomass in Saccharomyces cerevisiae increases recombinant protein yield:the use of a respiratory strain as a microbial cell factory

BACKGROUND: Recombinant protein production is universally employed as a solution to obtain the milligram to gram quantities of a given protein required for applications as diverse as structural genomics and biopharmaceutical manufacture. Yeast is a well-established recombinant host cell for these purposes. In this study we wanted to investigate whether our respiratory Saccharomyces cerevisiae strain, TM6*, could be used to enhance the productivity of recombinant proteins over that obtained from corresponding wild type, respiro-fermentative strains when cultured under the same laboratory conditions. RESULTS: Here we demonstrate at least a doubling in productivity over wild-type strains for three recombinant membrane proteins and one recombinant soluble protein produced in TM6* cells. In all cases, this was attributed to the improved biomass properties of the strain. The yield profile across the growth curve was also more stable than in a wild-type strain, and was not further improved by lowering culture temperatures. This has the added benefit that improved yields can be attained rapidly at the yeast's optimal growth conditions. Importantly, improved productivity could not be reproduced in wild-type strains by culturing them under glucose fed-batch conditions: despite having achieved very similar biomass yields to those achieved by TM6* cultures, the total volumetric yields were not concomitantly increased. Furthermore, the productivity of TM6* was unaffected by growing cultures in the presence of ethanol. These findings support the unique properties of TM6* as a microbial cell factory. CONCLUSIONS: The accumulation of biomass in yeast cell factories is not necessarily correlated with a proportional increase in the functional yield of the recombinant protein being produced. The respiratory S. cerevisiae strain reported here is therefore a useful addition to the matrix of production hosts currently available as its improved biomass properties do lead to increased volumetric yields without the need to resort to complex control or cultivation schemes. This is anticipated to be of particular value in the production of challenging targets such as membrane proteins.