Efficient and cost-effective experimental determination of kinetic constants and data: the success of a Bayesian systematic approach to drug transport, receptor binding, continuous culture and cell transport kinetics

Details about the parameters of kinetic systems are crucial for progress in both medical and industrial research, including drug development, clinical diagnosis and biotechnology applications. Such details must be collected by a series of kinetic experiments and investigations. The correct design of the experiment is essential to collecting data suitable for analysis, modelling and deriving the correct information. We have developed a systematic and iterative Bayesian method and sets of rules for the design of enzyme kinetic experiments. Our method selects the optimum design to collect data suitable for accurate modelling and analysis and minimises the error in the parameters estimated. The rules select features of the design such as the substrate range and the number of measurements. We show here that this method can be directly applied to the study of other important kinetic systems, including drug transport, receptor binding, microbial culture and cell transport kinetics. It is possible to reduce the errors in the estimated parameters and, most importantly, increase the efficiency and cost-effectiveness by reducing the necessary amount of experiments and data points measured. (C) 2003 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Neuromuscular junction morphology, fiber-type proportions, and satellite-cell proliferation rates are altered in MyoD(-/-) mice

Gene compensation by members of the myogenic regulatory factor (MRF) family has been proposed to explain the apparent normal adult phenotype of MyoD(-/-) mice. Nerve and field stimulation were used to investigate contraction properties of muscle from MyoD(-/-) mice, and molecular approaches were used to investigate satellite-cell behavior. We demonstrate that MyoD deletion results in major alterations in the organization of the neuromuscular junction, which have a dramatic influence on the physiological contractile properties of skeletal muscle. Second, we show that the lineage progression of satellite cells (especially initial proliferation) in the absence of MyoD is abnormal and linked to perturbations in the nuclear localization of beta-catenin, a key readout of canonical Wnt signaling. These results show that MyoD has unique functions in both developing and adult skeletal muscle that are not carried out by other members of the MRF family.

The price of space: the convergence of value in use and value in exchange

This paper discusses concepts of value from the point of view of the user of the space and the counter view of the provider of the same. Land and property are factors of production. The value of the land flows from the use to which it is put, and that in turn, is dependent upon the demand (and supply) for the product or service that is produced/provided from that space. If there is a high demand for the product (at a fixed level of supply), the price will increase and the economic rent for the land/property will increase accordingly. This is the underlying paradigm of Ricardian rent theory where the supply of land is fixed and a single good is produced. In such a case the rent of land is wholly an economic rent. Economic theory generally distinguishes between two kinds of price, price of production or “value in use” (as determined by the labour theory of value), and market price or “value in exchange” (as determined by supply and demand). It is based on a coherent and consistent theory of value and price. Effectively the distinction is between what space is ‘worth’ to an individual and that space’s price of exchange in the market place. In a perfect market where any individual has access to the same information as all others in the market, price and worth should coincide. However in a market where access to information is not uniform, and where different uses compete for the same space, it is more likely that the two figures will diverge. This paper argues that the traditional reliance of valuers to use methods of comparison to determine “price” has led to an artificial divergence of “value in use” and “value in exchange”, but now such comparison are becoming more difficult due to the diversity of lettings in the market place, there will be a requirement to return to fundamentals and pay heed to the thought process of the user in assessing the worth of the space to be let.

The role of rainfall intensity and soil in determining rates of flow through cryoturbated chalk

The effects of different water application rates (3, 10, 15 and 30 mm/h) and of topsoil removal on the rate of downward water movement through the cryoturbated chalk zone in southern England were investigated in situ. During and after each application of water, changes in water content and matric potential of the profile were monitored and percolate was collected in troughs. The measured water breakthrough time showed that water moved to 1.2 m depth quickly (in 8.2 h) even with application rate as low as 3 mm/h and that the time was only 3 h when water was applied at a rate of 15 mm/ h. These breakthrough times were about 150 and 422 fold shorter, respectively, than those expected if the water had been conducted by the matrix alone. Percolate was collected in troughs within 3.5 h at 1.2 m depth when water was applied at 30 mm/h and the quantity collected indicated that a significant amount of the surface applied water moved downward through inter-aggregate pores. The small increase in volumetric water content (about 3%) in excess of matrix water content resulted in a large increase in pore water velocities, from 0.20 to 5.3 m/d. The presence of soil layer had effect on the time taken for water to travel through the cryoturbated chalk layer and in the soil layer, water took about 1-2 h to pass thorough, depending on the intensity.

The relationship between community-based organisations and the effective management of coastal and marine resources in the Western Indian Ocean region

This study examines the relationship between community based organisations and marine and coastal resource management in the Western Indian Ocean Region.

Response to zinc deficiency of two rice lines with contrasting tolerance is determined by root growth maintenance and organic acid exudation rates, and not by zinc-transporter activity

Zinc (Zn)-deficient soils constrain rice (Oryza sativa) production and cause Zn malnutrition. The identification of Zn-deficiency-tolerant rice lines indicates that breeding might overcome these constraints. Here, we seek to identify processes underlying Zn-deficiency tolerance in rice at the physiological and transcriptional levels. A Zn-deficiency-tolerant line RIL46 acquires Zn more efficiently and produces more biomass than its nontolerant maternal line (IR74) at low Zn(ext) under field conditions. We tested if this was the result of increased expression of Zn(2+) transporters; increased root exudation of deoxymugineic acid (DMA) or low-molecular-weight organic acids (LMWOAs); and/or increased root production. Experiments were performed in field and controlled environment conditions. There was little genotypic variation in transcript abundance of Zn-responsive root Zn(2+)-transporters between the RIL46 and IR74. However, root exudation of DMA and LMWOA was greater in RIL46, coinciding with increased root expression of putative ligand-efflux genes. Adventitious root production was maintained in RIL46 at low Zn(ext), correlating with altered expression of root-specific auxin-responsive genes. Zinc-deficiency tolerance in RIL46 is most likely the result of maintenance of root growth, increased efflux of Zn ligands, and increased uptake of Zn-ligand complexes at low Zn(ext); these traits are potential breeding targets.

Bicorrelations and cross-bicorrelations as non-linearity tests and tools for exchange rate forecasting

This paper proposes and implements a new methodology for forecasting time series, based on bicorrelations and cross-bicorrelations. It is shown that the forecasting technique arises as a natural extension of, and as a complement to, existing univariate and multivariate non-linearity tests. The formulations are essentially modified autoregressive or vector autoregressive models respectively, which can be estimated using ordinary least squares. The techniques are applied to a set of high-frequency exchange rate returns, and their out-of-sample forecasting performance is compared to that of other time series models

Joint data assimilation of satellite reflectance and net ecosystem exchange data constrains ecosystem carbon fluxes at a high-elevation subalpine forest

We utilized an ecosystem process model (SIPNET, simplified photosynthesis and evapotranspiration model) to estimate carbon fluxes of gross primary productivity and total ecosystem respiration of a high-elevation coniferous forest. The data assimilation routine incorporated aggregated twice-daily measurements of the net ecosystem exchange of CO2 (NEE) and satellite-based reflectance measurements of the fraction of absorbed photosynthetically active radiation (fAPAR) on an eight-day timescale. From these data we conducted a data assimilation experiment with fifteen different combinations of available data using twice-daily NEE, aggregated annual NEE, eight-day f AP AR, and average annual fAPAR. Model parameters were conditioned on three years of NEE and fAPAR data and results were evaluated to determine the information content from the different combinations of data streams. Across the data assimilation experiments conducted, model selection metrics such as the Bayesian Information Criterion and Deviance Information Criterion obtained minimum values when assimilating average annual fAPAR and twice-daily NEE data. Application of wavelet coherence analyses showed higher correlations between measured and modeled fAPAR on longer timescales ranging from 9 to 12 months. There were strong correlations between measured and modeled NEE (R2, coefficient of determination, 0.86), but correlations between measured and modeled eight-day fAPAR were quite poor (R2 = −0.94). We conclude that this inability to determine fAPAR on eight-day timescale would improve with the considerations of the radiative transfer through the plant canopy. Modeled fluxes when assimilating average annual fAPAR and annual NEE were comparable to corresponding results when assimilating twice-daily NEE, albeit at a greater uncertainty. Our results support the conclusion that for this coniferous forest twice-daily NEE data are a critical measurement stream for the data assimilation. The results from this modeling exercise indicate that for this coniferous forest, average annuals for satellite-based fAPAR measurements paired with annual NEE estimates may provide spatial detail to components of ecosystem carbon fluxes in proximity of eddy covariance towers. Inclusion of other independent data streams in the assimilation will also reduce uncertainty on modeled values.

Be careful how you ask! Using focus groups and nominal group technique to explore the barriers to learning

Schools have a legal duty to make reasonable adjustments for disabled pupils who experience barriers to learning. Inclusive approaches to data collection ensure that the needs of all children who are struggling are not overlooked. However, it is important that the methods promote sustained reflection on the part of all children, do not inadvertently accentuate differences between pupils, and do not allow individual needs to go unrecognized. This paper examines more closely the processes involved in using Nominal Group Technique to collect the views of children with and without a disability on the difficulties experienced in school. Data were collected on the process as well as the outcomes of using this technique to examine how pupil views are transformed from the individual to the collective, a process that involves making the private, public. Contrasts are drawn with questionnaire data, another method of data collection favoured by teachers. Although more time-efficient this can produce unclear and cursory responses. The views that surface from pupils need also to be seen within the context of the ways in which schools customize the data collection process and the ways in which the format and organization of the activity impact on the responses and responsiveness of the pupils.

Thermal and visual performance of real and theoretical thermochromic glazing solutions for office buildings

Thermochromic windows are able to modulate their transmittance in both the visible and the near-infrared field as a function of their temperature. As a consequence, they allow to control the solar gains in summer, thus reducing the energy needs for space cooling. However, they may also yield a reduction in the daylight availability, which results in the energy consumption for indoor artificial lighting being increased. This paper investigates, by means of dynamic simulations, the application of thermochromic windows to an existing office building in terms of energy savings on an annual basis, while also focusing on the effects in terms of daylighting and thermal comfort. In particular, due attention is paid to daylight availability, described through illuminance maps and by the calculation of the daylight factor, which in several countries is subject thresholds. The study considers both a commercially available thermochromic pane and a series of theoretical thermochromic glazing. The expected performance is compared to static clear and reflective insulating glass units. The simulations are repeated in different climatic conditions, showing that the overall energy savings compared to clear glazing can range from around 5% for cold climates to around 20% in warm climates, while not compromising daylight availability. Moreover the role played by the transition temperature of the pane is examined, pointing out an optimal transition temperatures that is irrespective of the climatic conditions.

The effect of financial leverage on real and accrual-based earnings management

Past research has documented a substitution effect between real earnings management (RM) and accrual-based earnings management (AM), depending on relative costs. This study contributes to this research by examining whether levels of (and changes in) financial leverage have an impact on this empirically documented trade-off. We hypothesise that in the presence of high leverage, firms that engage in earnings manipulation tactics will exhibit a preference for RM due to a lower possibility—and subsequent costs—of getting caught. We show that leverage levels and increases positively and significantly affect upward RM, with no significant effect on income-increasing AM, while our findings point towards a complementarity effect between unexpected levels of RM and AM for firms with very high leverage levels and changes. This is interpreted as an indication that high leverage could attract heavy outsider scrutiny, making it necessary for firms to use both forms of earnings management in order to achieve earnings targets. Furthermore, we document that equity investors exhibit a significantly stronger penalising reaction to AM vs. RM, indicating that leverage-induced RM is not as easily detectable by market participants as debt-induced AM, despite the fact that the former could imply deviation from optimal business practices.

Effects of kinetin and nitrogen on growth rates, pigment and protein contents in wild and phycoerythrin-deficient strains of Hypnea musciformis (Rhodophyta)

Hypnea musciformis (Wulfen in Jacqu.) J.V. Lamour. is the main source for carrageenan production in Brazil and strains with selected characteristics could improve the production of raw material. The effects of kinetin on growth rates, morphology, protein content, and concentrations of pigments (chlorophyll a, phycoerythrin, phycocyanin, and allophycocyanin) were assessed in the wild strain (brown phenotype) and in the phycoerythrin-deficient strain (green phenotype) of H. musciformis. Concentrations of kinetin ranging from 0 to 50 mu M were tested in ASP 12-NTA synthetic medium with 10 mu M nitrate (N-limited) and 100 mu M nitrate (N-saturated). In N-limited condition, kinetin stimulated growth rates of the phycoerythrin-deficient strain and formation of lateral branches in both colour strains. Kinetin stimulated protein biosynthesis in both strains. However, differences between both nitrogen conditions were significant only in the phycoerythrin-deficient strain. In the wild strain, effects of kinetin on concentrations of phycobiliproteins were not significant in both nitrogen conditions, except for chlorophyll content. However, the phycoerythrin-deficient strain showed an opposite response, and kinetin stimulated the phycobiliprotein biosynthesis, with the highest concentrations of phycoerythrin in N-saturated medium, while the highest concentrations of allophycocyanin and phycocyanin were observed in N-limited medium. These results indicate that the effects of kinetin on growth, morphology, protein and phycobiliprotein contents are influenced by nitrogen availability, and the main nitrogen storage pools in phycoerythrin-deficient strain of H. musciformis submitted to N-limited conditions were phycocyanin and allophycocianin, the biosynthesis of which was enhanced by kinetin.