PKQuest: capillary permeability limitation and plasma protein binding – application to human inulin,dicloxacillin and ceftriaxone pharmacokinetics

Background  

It is generally assumed that the tissue exchange of antibiotics is flow limited (complete equilibration between the capillary and the tissue water). This assumption may not be valid if there is a large amount of plasma protein binding because the effective capillary permeability depends on the product of the intrinsic capillary permeability (PS) and the fraction of solute that is free in the blood (fw_B). PKQuest, a new generic physiologically based pharmacokinetic software routine (PBPK), provides a novel approach to modeling capillary permeability in which the only adjustable parameter is the PS of muscle.     

PKQuest: measurement of intestinal absorption and first pass metabolism – application to human ethanol pharmacokinetics

Background

PKQuest, a new physiologically based pharmacokinetic (PBPK) program, is applied to human ethanol data. The classical definition of first pass metabolism (FPM) based on the differences in the area under the curve (AUC) for identical intravenous and oral doses is invalid if the metabolism is non-linear (e.g. ethanol). Uncertainties in the measurement of FPM have led to controversy about the magnitude of gastric alcohol metabolism. PKQuest implements a new, rigorous definition of FPM based on finding the equivalent intravenous input function that would produce a blood time course identical to that observed for the oral intake. This input function equals the peripheral availability (PA) and the FPM is defined by: FPM = Total oral dose – PA. PKQuest also provides a quantitative measurement of the time course of intestinal absorption.

Methods

PKQuest was applied to previously published ethanol pharmacokinetic data.

Results

The rate of ethanol absorption is primarily limited by the rate of gastric emptying. For oral ethanol with a meal: absorption is slow (≈ 3 hours) and the fractional PKQuest FPM was 36% (0.15 gm/Kg dose) and 7% (0.3 gm/Kg). In contrast, fasting oral ethanol absorption is fast (≈ 50 minutes) and FPM is small.

Conclusions

The standard AUC and one compartment methods significantly overestimate the FPM. Gastric ethanol metabolism is not significant. Ingestion of a coincident meal with the ethanol can reduce the peak blood level by about 4 fold at low doses. PKQuest and all the examples are freely available on the web at http://www.pkquest.com.     

Somatic hybrids of Solanum tuberosum – application to genetics and breeding

Cultivated potato (Solanum tuberosum L.) is one of the first agricultural crops successfully cultured in vitro and used for obtaining of somatic hybrids. The review presents the current state of knowledge of somatic hybridisation involving this and other species from the genus of Solanum. Methods of somatic hybridisation, in particular factors that must be considered during designing the experiments are presented and discussed. The main attention however is focused on processes that are responsible for somatic hybrid formation. Complex interactions between genomes and plasmones lead to formation of symmetric, asymmetric and cytoplasmic recombinants. The concept of alloplasmic incompatibility is presented and discussed in relation to Solanum hybrids. Selected examples of potato somatic hybrids with agronomically important traits derived from wild species are presented in the table and discussed.     

Rhamnose lipids – biosynthesis, microbial production and application potential

Biosurfactants containing rhamnose and β-hydroxydecanoic acid and called rhamnolipids are reviewed with respect to microbial producers, their physiological role, biosynthesis and genetics, and especially their microbial overproduction, physicochemical properties and potential applications. With Pseudomonas species, more than 100 g l⁻¹ rhamnolipids were produced from 160 g l⁻¹ soybean oil at a volumetric productivity of 0.4 g l⁻¹h⁻¹. The individual rhamnolipids are able to lower the surface tension of water from 72 mN m⁻¹ to 25–30 mN m⁻¹ at concentrations of 10–200 mg l⁻¹. After initial testing, rhamnolipids seem to have potential applications in combating marine oil pollution, removing oil from sand and in combating zoosporic phytopathogens. Rhamnolipids are also a source of l-rhamnose, which is already used for the industrial production of high-quality flavor components. Received: 1 July 1998 / Received revision: 11 September 1998 / Accepted: 13 September 1998     

Fluxes of nitrous oxide, methane and carbon dioxide during freezing–thawing cycles in an Inner Mongolian steppe

Combined measurements of nitrification activity and N₂O emissions were performed in a lowland and a montane tropical rainforest ecosystem in NE-Australia over a 18 months period from October 2001 until May 2003. At both sites gross nitrification rates, measured by the BaPS technique, showed a strong seasonal pattern with significantly higher rates of gross nitrification during wet season conditions. Nitrification rates at the montane site (1.48?±?0.24–18.75?±?2.38 mg N kg^?1 day^?1) were found to be significantly higher than at the lowland site (1.65?±?0.21–4.54?±?0.27 mg N kg^?1 day^?1). The relationship between soil moisture and gross nitrification rates could be described best by O’Neill functions having a soil moisture optimum of nitrification at app. 65% WFPS. At the lowland site, for which continuous measurements of N₂O emissions were available, nitrification was positively correlated with N₂O emission. Nitrification contributed significantly to N₂O formation during dry season (app.85%) but less (app. 30%) during wet season conditions. In average 0.19‰ of the N metabolized by nitrification was released as N₂O. The N₂O fraction loss for nitrification was positively correlated with changes in soil moisture and varied slightly between 0.15 and 0.22‰. Our results demonstrate that combined N₂O emission and microbial N turnover studies covering prolonged observation periods are needed to clarify and quantify the role of the microbial processes nitrification and denitrification for annual N₂O emissions from soils of terrestrial ecosystems.     

Inhibition of benzene,toluene, phenol and benzoate in single and combination on Anammox activity: implication to the denitrification–Anammox synergy

A previous study demonstrated that denitrification synergized with Anammox could accelerate the anaerobic degradation of benzene. The inhibitory effects of benzene, toluene, phenol and benzoate in single and combination on Anammox activity were investigated by short-term batch tests. The results indicated that the inhibition of single compounds on Anammox could be well fitted with the extended non-competitive and Luong inhibition kinetic models. The inhibitions of the individual compound were in order as follows: benzene?>?toluene?>?phenol?>?benzoate. The joint inhibitions of bi-component mixtures of benzene with toluene, benzene with phenol and benzene with benzoate on Anammox activity were additive; the joint inhibition of a tri-component mixture (benzene, toluene and phenol) was partly additive; and the joint inhibition of a multicomponent mixture (benzene, toluene, phenol and benzoate) was synergistic. The effect of benzoate on the denitrification–Anammox synergy for benzene degradation was evaluated using a long-term test. Although the average rate of benzene degradation decreased by 13% with the addition of 10 mg L^?1 benzoate, the average rate of NO₃^? and NH₄⁺ increased by approximately 1- and 0.56-fold, respectively, suggesting that benzoate favors the stability of the denitrification–Anammox synergy. The carboxylation of benzene would be a more favorable pathway for the anaerobic degradation of benzene under denitrification synergized with Anammox.     

Effluxes of nitrous oxide,methane and carbon dioxide and their responses to increasing nitrogen deposition in the Gurbantünggüt Desert of Xinjiang,China北大核心CSCD

Aims Desert soils play an important role in the exchange of major greenhouse gas (GHG) between atmosphere and soil. However, many uncertainties existed in understanding of desert soil role, especially in efflux evaluation under a changing environment. Methods We conducted plot-based field study in center of the Gurbantünggüt Desert, Xinjiang, and applied six rates of simulated nitrogen (N) deposition on the plots, i.e. 0 (N0), 0.5 (N0.5), 1.0 (N1), 3.0 (N3), 6.0 (N6) and 24.0 (N24) g·m-2·a-1. The exchange rates of N2O, CH4 and CO2 during two growing seasons were measured for two years after N applications. Important findings The average efflux of two growing seasons from control plots (N0) were 4.8 μg·m-2·h-1, -30.5 μg·m-2·h-1 and 46.7 mg·m-2·h-1 for N2O, CH4 and CO2, respectively. The effluxes varied significantly among seasons. N0, N0.5 and N1 showed similar exchange of N2O in spring and summer, which was relatively higher than in autumn, while the rates of N2O in N6 and N24 were controled by time points of N applications. The uptake of CH4 was relatively higher in both spring and summer, and lower in autumn. Emission of CO2 changed minor from spring to summer, and greatly decreased in autumn in the first measured year. In the second year, the emission patterns were changed by rates of N added. N additions generally stimulated the emission of N2O, while the effects varied in different seasons and years. In addition, no obvious trends were found in the emission factor of N2O. The uptake of CH4 was not significantly affected by N additions. N additions did not change CO2 emissions in the first year, while high N significantly reduced the CO2 emissions in spring and summer of the second year, without affected in autumn. Structure equation model analysis on the factors suggested that N2O, CH4 and CO2 were dominantly affected by the N application rates, soil temperature or moisture and plant density, respectively. Over the growing seasons, both the net efflux and the global warming potential caused by N additions were small.     

Palladium – Decorated reduced graphene oxide/zinc oxide nanocomposite for enhanced antimicrobial,antioxidant and cytotoxicity activities

The one-step hydrothermal synthesis of Pd nanoparticles with RGO-ZnO nanocomposites finds promising applications in antimicrobial, antioxidant, cytotoxicity activities. Synthesized graphene oxide was mixed with ZnO, PdCl₄, to form Pd-RGO-ZnO nanocomposite, without using any chemical reductants. Nanocomposite was characterized by several techniques. X-ray diffraction (XRD) and X-ray photoelectron spectroscopic (XPS) analysis confirmed the successful deposition of Pd on the RGO-ZnO sheets. Fourier transform infrared spectroscopy (FT-IR), confirmed the presence of functional groups. Scanning electron microscopic (SEM) observations showed uniform morphology. The SAED patterns of the Transmission electron microscopic studies (TEM) revealed that the prepared Pd-RGO-ZnO nanocomposite patterns were recorded and it was represented to (200), (001), planes which were highly supported by its XRD analysis. Synthesized nanocomposites exhibited excellent performance towards biological activities.     

Systematic identifiability testing for unambiguous mechanistic modeling – application to JAK-STAT,MAP kinase,and NF-κB signaling pathway models

Background  

When creating mechanistic mathematical models for biological signaling processes it is tempting to include as many known biochemical interactions into one large model as possible. For the JAK-STAT, MAP kinase, and NF-κB pathways a lot of biological insight is available, and as a consequence, large mathematical models have emerged. For large models the question arises whether unknown model parameters can uniquely be determined by parameter estimation from measured data. Systematic approaches to answering this question are indispensable since the uniqueness of model parameter values is essential for predictive mechanistic modeling.     

Foliar application of urea to “Sauvignon Blanc” and “Merlot” vines: doses and time of application

A careful control of the N nutritional status of grapevines can have a determining effect on wine characteristics; therefore a suitable management of N fertilization might allow some wine parameters to be modified, thereby improving product quality. The aim of this study was to determine the effect of foliar application of urea at different doses and different times of the growing season on the parameters of Sauvignon Blanc and Merlot grape juice. The research described herein involved Sauvignon Blanc and Merlot grapevines (V. vinifera L.) at a commercial vineyard and was conducted over 2 years. In the first year, N treatment involved a foliar application at a dose of 10 kg N ha^?1 during veraison, whereas in the second year it involved a foliar urea application at two doses (10 and 50 kg N ha^?1) and at three different times—3 weeks before veraison, during veraison and 3 weeks after veraison. In this second year, the urea applied at a dose of 10 kg N ha^?1 was isotopically labelled with 1% ¹⁵N. Chemical parameters, yeast assimilable N, amino acid content, amino acid profile and N isotopic composition were determined for all treatments. Grape and grape-juice parameters for Merlot were found to be more affected by N fertilization than for Sauvignon Blanc and were also more affected during the second year than during the first year, thus indicating that the climatic characteristics of each campaign could affect these parameters. The yeast assimilable N in grape juice was found to be higher for late applications of foliar urea, with application of the higher dose of urea during veraison increasing the amino acid and proline contents in both varieties. The isotopic analysis data showed that the urea applied to leaves was transferred to the berries, with the maximum translocation in Sauvignon Blanc occurring for the post-veraison treatment and in Merlot for the veraison treatment. We can therefore conclude that foliar application of urea could modify grape juice quality and could therefore be used as a tool for obtaining quality wines.     

Aβ peptide interactions with isoflurane, propofol, thiopental and combined thiopental with halothane: A NMR study

Aβ peptide is the major component of senile plaques (SP) which accumulates in AD (Alzheimer's disease) brain. Reports from different laboratories indicate that anesthetics interact with Aβ peptide and induce Aβ oligomerization. The molecular mechanism of Aβ peptide interactions with these anesthetics was not determined. We report molecular details for the interactions of uniformly ¹⁵N labeled Aβ40 with different anesthetics using 2D nuclear magnetic resonance (NMR) experiments. At high concentrations both isoflurane and propofol perturb critical amino acid residues (G29, A30 and I31) of Aβ peptide located in the hinge region leading to Aβ oligomerization. In contrast, these three specific residues do not interact with thiopental and subsequently no Aβ oligomerization was observed. However, studies with combined anesthetics (thiopental and halothane), showed perturbation of these residues (G29, A30 and I31) and subsequently Aβ oligomerization was found. Perturbation of these specific Aβ residues (G29, A30 and I31) by different anesthetics could play an important role to induce Aβ oligomerization.     

Honey and diabetes mellitus: Obstacles and challenges – Road to be repaired

Background and objectiveSince ancient times, honey has been used due to its nutritional and therapeutic value. The role of honey has been acknowledged in the scientific literature however, its use has been controversially discussed and has not been well accepted in modern medicine especially for diabetic patients. This study aimed to investigate the role of honey in diabetic patients.MethodsIn this study, we identified 107 research articles from data based search engines including “PubMed”, “ISI-Web of Science”, “Embase” and “Google Scholar”. The research papers were selected by using the primary key-terms including “Honey”, “Honey bee” and “Diabetes Mellitus”. The research documents in which “Honey” and “Diabetes Mellitus” were debated are included. After screening, we reviewed 66 papers and finally we selected 35 studies which met the inclusion criteria and the remaining documents were excluded.ResultsThis study investigated the preclinical, clinical, human and animal model studies on honey and diabetes mellitus and found that honey decreases the fasting serum glucose, increases the sting C-peptide and 2-h postprandial C-peptide. Although, there is a dearth of data and literature also contrary discussed the use of honey in diabetic patients.ConclusionHoney decreases the fasting serum glucose, increases fasting C-peptide and 2-h postprandial C-peptide. Honey had low glycemic index and peak incremental index in diabetic patients. The use of honey in diabetic patients still has obstacles and challenges and needs more large sample sized, multi-center clinical controlled studies to reach better conclusions.     

Computational vascular fluid–structure interaction: methodology and application to cerebral aneurysms

A computational vascular fluid–structure interaction framework for the simulation of patient-specific cerebral aneurysm configurations is presented. A new approach for the computation of the blood vessel tissue prestress is also described. Simulations of four patient-specific models are carried out, and quantities of hemodynamic interest such as wall shear stress and wall tension are studied to examine the relevance of fluid–structure interaction modeling when compared to the rigid arterial wall assumption. We demonstrate that flexible wall modeling plays an important role in accurate prediction of patient-specific hemodynamics. Discussion of the clinical relevance of our methods and results is provided.     

Protein complex finding and ranking: An application to Alzheimer’s disease

Protein complexes are known to play a major role in controlling cellular activity in a living being. Identifying complexes from raw protein–protein interactions (PPIs) is an important area of research. Earlier work has been limited mostly to yeast and a few other model organisms. Such protein complex identification methods, when applied to large human PPIs often give poor performance. We introduce a novel method called ComFiR to detect such protein complexes and further rank diseased complexes based on a query disease. We have shown that it has better performance in identifying protein complexes from human PPI data. This method is evaluated in terms of positive predictive value, sensitivity and accuracy. We have introduced a ranking approach and showed its application on Alzheimer’s disease.     

TNF and TNF-receptors: From mediators of cell death and inflammation to therapeutic giants – past,present and future

Tumor Necrosis Factor (TNF), initially known for its tumor cytotoxicity, is a potent mediator of inflammation, as well as many normal physiological functions in homeostasis and health, and anti-microbial immunity. It also appears to have a central role in neurobiology, although this area of TNF biology is only recently emerging. Here, we review the basic biology of TNF and its normal effector functions, and discuss the advantages and disadvantages of therapeutic neutralization of TNF – now a commonplace practice in the treatment of a wide range of human inflammatory diseases. With over ten years of experience, and an emerging range of anti-TNF biologics now available, we also review their modes of action, which appear to be far more complex than had originally been anticipated. Finally, we highlight the current challenges for therapeutic intervention of TNF: (i) to discover and produce orally delivered small molecule TNF-inhibitors, (ii) to specifically target selected TNF producing cells or individual (diseased) tissue targets, and (iii) to pre-identify anti-TNF treatment responders. Although the future looks bright, the therapeutic modulation of TNF now moves into the era of personalized medicine with society's challenging expectations of durable treatment success and of achieving long-term disease remission.     

Semiempirical configuration interaction calculations in biochemical environments: parametrization and application to γD-crystallin, an eye-lens protein

We approach the problem of optical excitations in molecular aggregates in complex biochemical environments from a computational, all-atom perspective. The system is divided into a π orbital part described by a Pariser-Parr-Pople model with configuration interaction using singly excited Slater determinants (PPP-CIS). It is coupled to the protein and water charges of a classical force field. Strategies for a high-accuracy reparameterization and an efficient computational solution are presented. For γD-crystallin, a band edge consisting of charge-transfer states emerges for a coupled molecular aggregate compared to the uncoupled residues. The energies of some charge-transfer states strongly depend on the dielectric properties of the model, giving a first insight into the potential temporal evolution of these excitations. Possible biochemical implications are discussed.     

Nitric oxide and cytochrome oxidase: substrate,inhibitor or effector?

Endogenously produced nitric oxide (NO) controls oxygen consumption by inhibiting cytochrome c oxidase, the terminal electron acceptor of the mitochondrial electron transport chain. The oxygen-binding site of the enzyme is an iron/copper (haem a3/CuB) binuclear centre. At high substrate (ferrocytochrome c) concentrations, NO binds reversibly to the reduced iron in competition with oxygen. At low substrate concentrations, NO binds to the oxidized copper. Inhibition at the haem iron site is relieved by dissociation of the NO from the reduced iron. Inhibition at the copper site is relieved by oxidation of the bound NO and subsequent dissociation of nitrite from the enzyme. Therefore, NO can be a substrate, inhibitor or effector of cytochrome oxidase, depending on cellular conditions.