Summary• Whereas mycorrhizal fungi are acknowledged to be the sources of nitrogen (N) and carbon (C) in achlorophyllous (myco-heterotrophic) orchids, the sources of these elements in autotrophic orchids are unknown. We have determined the stable isotope abundance of N and C to quantify their gain from different sources in these two functional groups and in non-orchids of distinctive mycorrhizal types.• Leaves of each plant were collected from four forest and four grassland sites in Europe. The N and C isotope abundance, and total N concentrations of their tissues and of associated soils were determined.• Myco-heterotrophic orchids were significantly more enriched in 15 N ( ε MHO-R = 11.5‰) and 13 C ( ε MHO-R = 8.4‰) than co-occurring non-orchids. δ 15 N and δ 13 C signatures of autotrophic orchids ranged from values typical of non-orchids to those more representative of myco-heterotrophic orchids.• Utilization of fungi-derived N and C probably explains the relative 15 N and 13 C enrichment in the myco-heterotrophs. A linear two-source isotopic mixing model was used to estimate N and C gain of autotrophic orchids from their fungal associates. Of the putatively autotrophic species, Cephalanthera damasonium obtained the most N and C by the fungal route, but several other species also fell into the partially myco-heterotrophic category.

The presented results facilitate the integration of pregnancy-dependent changes in anatomy and physiology into mechanistic population physiologically based pharmacokinetic models. Such models can ultimately provide a valuable tool to investigate the pharmacokinetics during pregnancy in silico and support informed decision making regarding optimal dosing regimens in this vulnerable special population.

The primary electron transfer in reaction centers ofRhodobacter sphaeroides is studied by subpicosecond absorption spectroscopy with polarized light in the spectral range of 920-1040 nm. Here the bacteriochlorophyll anion radical has an absorption band while the other pigments of the reaction center have vanishing ground-state absorption. The transient absorption data exhibit a pronounced 0.9-ps kinetic component which shows a strong dichroism. Evaluation of the data yields an angle between the transition moments of the special pair and the species related with the 0.9-ps kinetic component of 26 ± 8. This angle compares favorably with the value of 29°expected for the reduced accessory bacteriochlorophyll. Extensive transient absorbance data are fufly consistent with a stepwise electron ransfer via the accessory bacteriochlorophyll.In the primary processes of bacterial photosynthesis, absorbed light energy is stored via an electron transfer within the reaction center (RC). While the molecular structure of two bacterial reaction centers has been known for a number of years (1-3), the detailed molecular mechanism of the electron transfer is still the subject of intense investigations (4-20). There is general agreement that the first electron transfer process starts at a pair of bacteriochlorophyll (BChl) molecules-the special pair P-which acts as the primary donor. The

The modification of reaction centers from Rhodobacter sphaeroides by the introduction of pheophytins instead of bacteriopheophytins leads to interesting changes in the primary photosynthetic reaction: long-living populations of the excited electronic state of the special pair P* and the bacteriochlorophyll anion Bi show up. The data allow the determination of the energetics in the reaction center. The free energy of the first intermediate P+Br , where the electron has reached the accessory bacteriochlorophyll BA lies = 450 cm-' below the initially excited special pair P*.

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Pregnancy population PBPK models can provide a valuable tool to predict a priori the pharmacokinetics of predominantly renally cleared drugs in pregnant women. These models can ultimately support informed decision making regarding optimal dosing regimens in this vulnerable special population.

ABSTRACT:Active processes involved in drug metabolization and distribution mediated by enzymes, transporters, or binding partners mostly occur simultaneously in various organs. However, a quantitative description of active processes is difficult because of limited experimental accessibility of tissue-specific protein activity in vivo. In this work, we present a novel approach to estimate in vivo activity of such enzymes or transporters that have an influence on drug pharmacokinetics. Tissue-specific mRNA expression is used as a surrogate for protein abundance and activity and is integrated into physiologically based pharmacokinetic (PBPK) models that already represent detailed anatomical and physiological information. The new approach was evaluated using three publicly available databases: whole-genome expression microarrays from ArrayExpress, reverse transcription-polymerase chain reaction-derived gene expression estimates collected from the literature, and expressed sequence tags from UniGene. Expression data were preprocessed and stored in a customized database that was then used to build PBPK models for pravastatin in humans. These models represented drug uptake by organic anion-transporting polypeptide 1B1 and organic anion transporter 3, active efflux by multidrug resistance protein 2, and metabolization by sulfotransferases in liver, kidney, and/or intestine. Benchmarking of PBPK models based on gene expression data against alternative models with either a less complex model structure or randomly assigned gene expression values clearly demonstrated the superior model performance of the former. Besides accurate prediction of drug pharmacokinetics, integration of relative gene expression data in PBPK models offers the unique possibility to simultaneously investigate drug-drug interactions in all relevant organs because of the physiological representation of protein-mediated processes.

BackgroundBecause of the vulnerability and frailty of elderly adults, clinical drug development has traditionally been biased towards young and middle-aged adults. Recent efforts have begun to incorporate data from paediatric investigations. Nevertheless, the elderly often remain underrepresented in clinical trials, even though persons aged 65 years and older receive the majority of drug prescriptions. Consequently, a knowledge gap exists with regard to pharmacokinetic (PK) and pharmacodynamic (PD) responses in elderly subjects, leaving the safety and efficacy of medicines for this population unclear.ObjectivesThe goal of this study was to extend a physiologically based pharmacokinetic (PBPK) model for adults to encompass the full course of healthy aging through to the age of 100 years, to support dose selection and improve pharmacotherapy for the elderly age group.MethodsFor parameterization of the PBPK model for healthy aging individuals, the literature was scanned for anthropometric and physiological data, which were consolidated and incorporated into the PBPK software PK-Sim®. Age-related changes that occur from 65 to 100 years of age were the main focus of this work. For a sound and continuous description of an aging human, data on anatomical and physiological changes ranging from early adulthood to old age were included. The capability of the PBPK approach to predict distribution and elimination of drugs was verified using the test compounds morphine and furosemide, administered intravenously. Both are cleared by a single elimination pathway. PK parameters for the two compounds in younger adults and elderly individuals were obtained from the literature. Matching virtual populations—with regard to age, sex, anthropometric measures and dosage—were generated. Profiles of plasma drug concentrations over time, volume of distribution at steady state (V ss) values and elimination half-life (t ½) values from the literature were compared with those predicted by PBPK simulations for both younger adults and the elderly.ResultsFor most organs, the age-dependent information gathered in the extensive literature analysis was dense. In contrast, with respect to blood flow, the literature study produced only sparse data for several tissues, and in these cases, linear regression was required to capture the entire elderly age range. On the basis of age-informed physiology, the predicted PK profiles described age-associated trends well. The root mean squared prediction error for the prediction of plasma concentrations of furosemide and morphine in the elderly were improved by 32 and 49 %, respectively, by use of age-informed physiology. The majority of the individual V ss and t ½ values for the two model compounds, furosemide and morphine, were well predicted in the elderly population, except for long furosemide half-lifes.ConclusionThe results of this study support the feasibility of using a knowledge-driven PBPK aging model that includes the elderly to predict PK alterations throughout the entire course of aging, and thus to...