Do changes in transglutaminase activity alter latent transforming growth factor beta activation in experimental diabetic nephropathy?

Background. Diabetic nephropathy is the leading cause of end-stage kidney failure worldwide. It is characterized by excessive extracellular matrix accumulation. Transforming growth factor beta 1 (TGF-ß1) is a fibrogenic cytokine playing a major role in the healing process and scarring by regulating extracellular matrix turnover, cell proliferation and epithelial mesanchymal transdifferentiation. Newly synthesized TGF-ß is released as a latent, biologically inactive complex. The cross-linking of the large latent TGF-ß to the extracellular matrix by transglutaminase 2 (TG2) is one of the key mechanisms of recruitment and activation of this cytokine. TG2 is an enzyme catalyzing an acyl transfer reaction leading to the formation of a stable e(?-glutamyl)-lysine cross-link between peptides.Methods. To investigate if changes in TG activity can modulate TGF-ß1 activation, we used the mink lung cell bioassay to assess TGF-ß activity in the streptozotocin model of diabetic nephropathy treated with TG inhibitor NTU281 and in TG2 overexpressing opossum kidney (OK) proximal tubular epithelial cells.Results. Application of the site-directed TG inhibitor NTU281 caused a 25% reduction in kidney levels of active TGF-ß1. Specific upregulation of TG2 in OK proximal tubular epithelial cells increased latent TGF-ß recruitment and activation by 20.7% and 19.7%, respectively, in co-cultures with latent TGF-ß binding protein producing fibroblasts.Conclusions. Regulation of TG2 directly influences the level of active TGF-ß1, and thus, TG inhibition may exert a renoprotective effect by targeting not only a direct extracellular matrix deposition but also TGF-ß1 activation and recruitment.

Simulation modeling of phytoplankton dynamics in a large eutrophic river, Hungary – Danubian Phytoplankton Growth Model (DPGM)

Ecological models have often been used in order to answer questions that are in the limelight of recent researches such as the possible effects of climate change. The methodology of tactical models is a very useful tool comparison to those complex models requiring relatively large set of input parameters. In this study, a theoretical strategic model (TEGM ) was adapted to the field data on the basis of a 24-year long monitoring database of phytoplankton in the Danube River at the station of G¨od, Hungary (at 1669 river kilometer – hereafter referred to as “rkm”). The Danubian Phytoplankton Growth Model (DPGM) is able to describe the seasonal dynamics of phytoplankton biomass (mg L−1) based on daily temperature, but takes the availability of light into consideration as well. In order to improve fitting, the 24-year long database was split in two parts in accordance with environmental sustainability. The period of 1979–1990 has a higher level of nutrient excess compared with that of the 1991–2002. The authors assume that, in the above-mentioned periods, phytoplankton responded to temperature in two different ways, thus two submodels were developed, DPGM-sA and DPGMsB. Observed and simulated data correlated quite well. Findings suggest that linear temperature rise brings drastic change to phytoplankton only in case of high nutrient load and it is mostly realized through the increase of yearly total biomass.

Differences in grain growth of calcite: a field-based modeling approach

Normal grain growth of calcite was investigated by combining grain size analysis of calcite across the contact aureole of the Adamello pluton, and grain growth modeling based on a thermal model of the surroundings of the pluton. In an unbiased model system, i.e., location dependent variations in temperature-time path, 2/3 and 1/3 of grain growth occurs during pro- and retrograde metamorphism at all locations, respectively. In contrast to this idealized situation, in the field example three groups can be distinguished, which are characterized by variations in their grain size versus temperature relationships: Group I occurs at low temperatures and the grain size remains constant because nano-scale second phase particles of organic origin inhibit grain growth in the calcite aggregates under these conditions. In the presence of an aqueous fluid, these second phases decay at a temperature of about 350 °C enabling the onset of grain growth in calcite. In the following growth period, fluid-enhanced group II and slower group III growth occurs. For group II a continuous and intense grain size increase with T is typical while the grain growth decreases with T for group III. None of the observed trends correlate with experimentally based grain growth kinetics, probably due to differences between nature and experiment which have not yet been investigated (e.g., porosity, second phases). Therefore, grain growth modeling was used to iteratively improve the correlation between measured and modeled grain sizes by optimizing activation energy (Q), pre-exponential factor (k0) and grain size exponent (n). For n=2, Q of 350 kJ/mol, k0 of 1.7×1021 μmns−1 and Q of 35 kJ/mol, k0 of 2.5×10-5 μmns−1 were obtained for group II and III, respectively. With respect to future work, field-data based grain growth modeling might be a promising tool for investigating the influences of secondary effects like porosity and second phases on grain growth in nature, and to unravel differences between nature and experiment.

FLOOD RISK ASSESSMENT UNDER HISTORICAL AND PREDICTED LAND USE CHANGE USING CONTINUOUS HYDROLOGIC MODELING

Current procedures for flood risk estimation assume flood distributions are stationary over time, meaning annual maximum flood (AMF) series are not affected by climatic variation, land use/land cover (LULC) change, or management practices. Thus, changes in LULC and climate are generally not accounted for in policy and design related to flood risk/control, and historical flood events are deemed representative of future flood risk. These assumptions need to be re-evaluated, however, as climate change and anthropogenic activities have been observed to have large impacts on flood risk in many areas. In particular, understanding the effects of LULC change is essential to the study and understanding of global environmental change and the consequent hydrologic responses. The research presented herein provides possible causation for observed nonstationarity in AMF series with respect to changes in LULC, as well as a means to assess the degree to which future LULC change will impact flood risk. Four watersheds in the Midwest, Northeastern, and Central United States were studied to determine flood risk associated with historical and future projected LULC change. Historical single framed aerial images dating back to the mid-1950s were used along with Geographic Information Systems (GIS) and remote sensing models (SPRING and ERDAS) to create historical land use maps. The Forecasting Scenarios of Future Land Use Change (FORE-SCE) model was applied to generate future LULC maps annually from 2006 to 2100 for the conterminous U.S. based on the four IPCC-SRES future emission scenario conditions. These land use maps were input into previously calibrated Soil and Water Assessment Tool (SWAT) models for two case study watersheds. In order to isolate effects of LULC change, the only variable parameter was the Runoff Curve Number associated with the land use layer. All simulations were run with daily climate data from 1978-1999, consistent with the 'base' model which employed the 1992 NLCD to represent 'current' conditions. Output daily maximum flows were converted to instantaneous AMF series and were subsequently modeled using a Log-Pearson Type 3 (LP3) distribution to evaluate flood risk. Analysis of the progression of LULC change over the historic period and associated SWAT outputs revealed that AMF magnitudes tend to increase over time in response to increasing degrees of urbanization. This is consistent with positive trends in the AMF series identified in previous studies, although there are difficulties identifying correlations between LULC change and identified change points due to large time gaps in the generated historical LULC maps, mainly caused by unavailability of sufficient quality historic aerial imagery. Similarly, increases in the mean and median AMF magnitude were observed in response to future LULC change projections, with the tails of the distributions remaining reasonably constant. FORE-SCE scenario A2 was found to have the most dramatic impact on AMF series, consistent with more extreme projections of population growth, demands for growing energy sources, agricultural land, and urban expansion, while AMF outputs based on scenario B2 showed little changes for the future as the focus is on environmental conservation and regional solutions to environmental issues.

Ability of silver-impregnated contact lenses to control microbial growth and colonisation

Purpose: To examine the ability of silver nano-particles to prevent the growth of Pseudomonas aeruginosa and Staphylococcus aureus in solution or when adsorbed into contact lenses. To examine the ability of silver nano-particles to prevent the growth of Acanthamoeba castellanii. ----- ----- Methods: Etafilcon A lenses were soaked in various concentrations of silver nano-particles. Bacterial cells were then exposed to these lenses, and numbers of viable cells on lens surface or in solution compared to etafilcon A lenses not soaked in silver. Acanthamoeba trophozoites were exposed to silver nano-particles and their ability to form tracks was examined. ----- ----- Results: Silver nano-particle containing lenses reduced bacterial viability and adhesion. There was a dose-dependent response curve, with 10 ppm or 20 ppm silver showing > 5 log reduction in bacterial viability in solution or on the lens surface. For Acanthamoeba, 20 ppm silver reduced the ability to form tracks by approximately 1 log unit. ----- ----- Conclusions: Silver nanoparticles are effective antimicrobial agents, and can reduce the ability of viable bacterial cells to colonise contact lenses once incorporated into the lens.----- ----- Resumen: Objetivos: Examinar la capacidad de las nanopartículas de plata para prevenir el crecimiento de Pseudomonas aeruginosa y Staphylococcus aureus en soluciones para lentes de contacto o cuando éstas las adsorben. Examinar la capacidad de las nanopartículas de plata para prevenir el crecimiento de Acanthamoeba castellanii.----- ----- Métodos: Se sumergieron lentes etafilcon A en diversas concentraciones de nanopartículas de plata. Las células bacterianas fueron posteriormente expuestas a dichas lentes, y se compararon cantidades de células viables en la superficie de la lente o en la solución con las presentes en lentes etafilcon A que no habían sido sumergidas en plata. Trofozoítos de Acanthamoeba fueron expuestos a nanopartículas de plata y se examinó su capacidad para formar quistes.----- ----- Resultados: Las lentes que contienen nanopartículas de plata redujeron la viabilidad bacteriana y la adhesión. Hubo una curva de respuesta dependiente de la dosis, en la que 10 ppm o 20 ppm de plata mostró una reducción logarítmica > 5 en la viabilidad bacteriana tanto en la solución como en la superficie de la lente. Para Acanthamoeba, 20 ppm de plata redujeron la capacidad de formar quistes en aproximadamente 1 unidad logarítmica.----- ----- Conclusiones: Las nanopartículas de plata son agentes antimicrobianos eficaces y pueden reducir la capacidad de células bacterianas viables para colonizar las lentes de contacto una vez que se han incorporado en la lente.

Modeling prostate cancer: a perspective on transgenic mouse models

Despite considerable success in treatment of early stage localized prostate cancer (PC), acute inadequacy of late stage PC treatment and its inherent heterogeneity poses a formidable challenge. Clearly, an improved understanding of PC genesis and progression along with the development of new targeted therapies are warranted. Animal models, especially, transgenic immunocompetent mouse models, have proven to be the best ally in this respect. A series of models have been developed by modulation of expression of genes implicated in cancer-genesis and progression; mainly, modulation of expression of oncogenes, steroid hormone receptors, growth factors and their receptors, cell cycle and apoptosis regulators, and tumor suppressor genes have been used. Such models have contributed significantly to our understanding of the molecular and pathological aspects of PC initiation and progression. In particular, the transgenic mouse models based on multiple genetic alterations can more accurately address the inherent complexity of PC, not only in revealing the mechanisms of tumorigenesis and progression but also for clinically relevant evaluation of new therapies. Further, with advances in conditional knockout technologies, otherwise embryonically lethal gene changes can be incorporated leading to the development of new generation transgenics, thus adding significantly to our existing knowledge base. Different models and their relevance to PC research are discussed.

Stochastic analysis of the VEGF receptor response curve

Recently, an analysis of the response curve of the vascular endothelial growth factor (VEGF) receptor and its application to cancer therapy was described in [T. Alarcón, and K. Page, J. R. Soc. Lond. Interface 4, 283–304 (2007)]. The analysis is significantly extended here by demonstrating that an alternative computational strategy, namely the Krylov FSP algorithm for the direct solution of the chemical master equation, is feasible for the study of the receptor model. The new method allows us to further investigate the hypothesis of symmetry in the stochastic fluctuations of the response. Also, by augmenting the original model with a single reversible reaction we formulate a plausible mechanism capable of realizing a bimodal response, which is reported experimentally but which is not exhibited by the original model. The significance of these findings for mechanisms of tumour resistance to antiangiogenic therapy is discussed.

Navigational safety in port waters: Techniques for modeling collision risk

Navigational collisions are one of the major safety concerns for many seaports. Continuing growth of shipping traffic in number and sizes is likely to result in increased number of traffic movements, which consequently could result higher risk of collisions in these restricted waters. This continually increasing safety concern warrants a comprehensive technique for modeling collision risk in port waters, particularly for modeling the probability of collision events and the associated consequences (i.e., injuries and fatalities). A number of techniques have been utilized for modeling the risk qualitatively, semi-quantitatively and quantitatively. These traditional techniques mostly rely on historical collision data, often in conjunction with expert judgments. However, these techniques are hampered by several shortcomings, such as randomness and rarity of collision occurrence leading to obtaining insufficient number of collision counts for a sound statistical analysis, insufficiency in explaining collision causation, and reactive approach to safety. A promising alternative approach that overcomes these shortcomings is the navigational traffic conflict technique (NTCT), which uses traffic conflicts as an alternative to the collisions for modeling the probability of collision events quantitatively. This article explores the existing techniques for modeling collision risk in port waters. In particular, it identifies the advantages and limitations of the traditional techniques and highlights the potentials of the NTCT in overcoming the limitations. In view of the principles of the NTCT, a structured method for managing collision risk is proposed. This risk management method allows safety analysts to diagnose safety deficiencies in a proactive manner, which consequently has great potential for managing collision risk in a fast, reliable and efficient manner.

A qualitative approach to assessing the validity of the posttraumatic growth inventory

The Posttraumatic Growth Inventory (PTGI; Tedeschi & Calhoun, 1996) is the most commonly used measure of positive psychological change that can result from negotiating a traumatic experience. Whilst the PTGI has strong internal reliability, validity studies are still sparse. The presented research details trauma survivors’ understanding of items comprising the PTGI in order to qualitatively assess content validity. Participants were 14 trauma survivors who completed the PTGI and participated in a semi-structured interview. Thematic Analysis was conducted on participant’s transcribed interviews. One latent theme was identified reflecting that questions were consistently understood. A relationship was found between the constituent themes identified and the five factors of the PTGI. Participants answered the PTGI statements in a way that is consistent with the purpose of the instrument with only a small discrepancy found when some participants used the PTGI scale to indicate when a decrease in an element of the inventory had been experienced. Overall results supported the content validity of the PTGI.

Morphology-based model for predicting osteocyte-like cell line (MLO-Y4) growth process

This work has led to the development of empirical mathematical models to quantitatively predicate the changes of morphology in osteocyte-like cell lines (MLO-Y4) in culture. MLO-Y4 cells were cultured at low density and the changes in morphology recorded over 11 hours. Cell area and three dimensional shape features including aspect ratio, circularity and solidity were then determined using widely accepted image analysis software (ImageJTM). Based on the data obtained from the imaging analysis, mathematical models were developed using the non-linear regression method. The developed mathematical models accurately predict the morphology of MLO-Y4 cells for different culture times and can, therefore, be used as a reference model for analyzing MLO-Y4 cell morphology changes within various biological/mechanical studies, as necessary.

Deposition of hydrocarbon molecules on diamond (001) surfaces : atomic scale modeling

The impact induced chemisorption of hydrocarbon molecules (CH3 and CH2) on H-terminated diamond (001)-(2x1) surface was investigated by molecular dynamics simulation using the many-body Brenner potential. The deposition dynamics of the CH3 radical at impact energies of 0.1-50 eV per molecule was studied and the energy threshold for chemisorption was calculated. The impact-induced decomposition of hydrogen atoms and the dimer opening mechanism on the surface was investigated. Furthermore, the probability for dimer opening event induced by chemisorption of CH, was simulated by randomly varying the impact position as well as the orientation of the molecule relative to the surface. Finally, the energetic hydrocarbons were modeled, slowing down one after the other to simulate the initial fabrication of diamond-like carbon (DLC) films. The structure characteristic in synthesized films with different hydrogen flux was studied. Our results indicate that CH3, CH2 and H are highly reactive and important species in diamond growth. Especially, the fraction of C-atoms in the film having sp(3) hybridization will be enhanced in the presence of H atoms, which is in good agreement with experimental observations. (C) 2002 Elsevier Science B.V. All rights reserved.

Diurnal rhythm and effects of feeding, exercise and recombinant equine growth hormone on serum insulin concentrations in the horse

Reasons for performing the study As growth hormone increases lean body mass, it could be a therapy for obese horses. However, growth hormone use induces hyperinsulinaemia in some species, so further investigation is warranted. Objectives To investigate the effects of feeding, exercise and growth hormone therapy on basal insulin concentrations in healthy horses. Study design In vivo experimental study. Methods Blood samples were obtained every 30 min from 12 geldings over 24 h, to establish basal serum insulin concentrations, before they underwent a 3-week exercise programme. Horses were allocated into 2 groups and exercised for another 4 weeks. Group A received daily i.m. injections of recombinant equine growth hormone; 5 mg/day for 5 days, then 12.5 mg/day for 16 days. Blood samples were taken daily before feeding. Insulin vs. time area under curve of Groups A and B were compared using a Student's unpaired t test. Results Horses demonstrated insulin peaks within 2 h of feeding of 577 ± 108.3 pmol/l at 09.30 h and 342.4 ± 75.7 pmol/l at 17.30 h, despite receiving the same meal. The nadir was between midnight and 07.30 h. Exercise had no effect on basal insulin concentrations prior to equine growth hormone administrations. The equine growth hormone injections increased serum insulin concentrations (P = 0.01) within Group A, from 44.4 ± 15.3 pmol/l initially to 320.9 ± 238.2 pmol/l by Day 12. Exogenous growth hormone caused variable hyperinsulinaemia, which was alleviated once equine growth hormone administration ceased. Conclusions Single serum samples taken prior to the morning meal provide basal insulin concentrations. Exercise did not change basal insulin concentrations. However, equine growth hormone injections increased basal insulin concentrations, which were not ameliorated by exercise. Potential relevance This therapy is not recommended to address obesity in insulin-resistant equids.

Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: Results from two phase I studies

Purpose: PTK787/ZK 222584 (PTK/ZK), an orally active inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, inhibits VEGF-mediated angiogenesis. The pharmacodynamic effects of PTK/ZK were evaluated by assessing changes in contrast-enhancement parameters of metastatic liver lesions using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in patients with advanced colorectal cancer treated in two ongoing, dose-escalating phase I studies. Patients and Methods: Twenty-six patients had DCE-MRI performed at baseline, day 2, and at the end of each 28-day cycle. Doses of oral PTK/ZK ranged from 50 to 2000 mg once daily. Tumor permeability and vascularity were assessed by calculating the bidirectional transfer constant (Ki). The percentage of baseline Ki (% of baseline Ki) at each time point was compared with pharmacokinetic and clinical end points. Results: A significant negative correlation exists between the % of baseline Ki and increase in PTK/ZK oral dose and plasma levels (P = .01 for oral dose; P = .0001 for area under the plasma concentration curve at day 2). Patients with a best response of stable disease had a significantly greater reduction in Ki at both day 2 and at the end of cycle 1 compared with progressors (mean difference in % of baseline Ki, 47%, P = .004%; and 51%, P = .006; respectively). The difference in % of baseline Ki remained statistically significant after adjusting for baseline WHO performance status. Conclusion: These findings should help to define a biologically active dose of PTK/ZK. These results suggest that DCE-MRI may be a useful biomarker for defining the pharmacological response and dose of angiogenesis inhibitiors, such as PTK/ZK, for further clinical development. © 2003 by American Society of Clinical Oncology.