Binding of metals to macromolecular organic acids in natural waters

Trace metal speciation and bioavailability have become keys to current day toxicity and risk assessments. For many metals, macromolecular organic acids constitute the major ligand in fresh water and soil solution. Therefore, understanding their characteristics and behaviour is necessary for understanding trace metal behaviour. This study comprises investigations of the proton- and copper-binding properties of hydrophobic and hydrophilic dissolved organic matter fractions, and competition effects of iron(III) and aluminium. The solutions studied were a forest floor solution and a municipal solid waste incinerator bottom ash leachate. Two geochemical models (SHM and NICA-Donnan) were tested and calibrated against the experimental data. A structural analysis of the binding mode of iron(III) to fulvic acid in acid aqueous solutions was made using extended X-ray absorption fine structure (EXAFS) spectroscopy. Dissolved organic carbon (DOC) in the bottom ash leachate had fulvic acid-like properties and was dominated by the hydrophilic acid fraction. Three organic fractions (hydrophobic, transphilic and hydrophilic) were isolated from the forest floor solution using an XAD-8/XAD-4 tandem. All fractions were characterised by distinct but differing proton-binding properties, suggesting a more acidic character than 'generic' fulvic acid. The copper-binding isotherms were very similar for all three fractions and suggested strong copper binding to a small number of sites. In general, both models tested could be adjusted to obtain good fits to data on both proton- and copper-binding, but iron(III) and aluminium competition was better predicted by the SHM than the NICA-Donnan model. Only mononuclear iron(III) complexes were included in the model calculations, as the EXAFS study showed that these ¬dominated in the aqueous phase. Studies on untreated soil solution indicated that the three isolated fractions were the only contributors to the observed copper binding and together constitute the 'active' DOC fraction. Thus, combination of Leenheer fractionation data with the model parameters derived in this study is recommended for improved predictions of trace metal speciation in soil solutions. However, further studies along this research line, including other samples and trace metals, are highly recommended

Оформление конструкторской документации на печатные платы в условиях автоматизированного проектирования и подготовки производства

Предложен подход к оформлению чертежей печатных плат, позволяющий значительно упростить документацию, а также упорядочить документооборот

Medication adjustments in 1 out 3 patients as a result of pharmacogenetic testing initiated by primary care pharmacists based on specific inclusion protocols (SA-PGx pilot)

Medication adjustments in 7 out of 3 patients as a result of pharmacogenetic testing initiated by primary care pharmacists based on specific inclusion protocols (SA-PGx pilot) Background Pharmacogenetic analysis is currently performed at 16 certified laboratories in the Netherlands. For 90 different drugs pharmacogenetic advice is available, of which 23 drugs are frequently prescribed in primary care. Despite these opportunities the use of pharmacogenetic testing in primary care is still limited. Objective Investigate to what extent pharmacogenetic inclusion protocols and expert opinion of a pharmacist will lead to medication adjustments in patients. Design Prospective feasibility cohort study. Methods Eligible patients for pharmacogenetic testing are selected based on predefined inclusion protocols or pharmacist's expert opinion. DNA analysis is performed on buccal swab material collected in the pharmacy. Questionnaires, regarding drug-related complaints and patient satisfaction concerning provided care in the pharmacy, are filled in by the patients at baseline and after 1-2 weeks (no medication adjustments) or after 6 weeks (medication adjustments). Following study completion the application of pharmacogenetic testing is evaluated by the participating pharmacists. Results Over a period of 2 years 86 patients were included within 10 primary care pharmacies. Medication changes based on pharmacogenetic results were registered in 25 patients (29%). Almost 1/3 of these patients were selected based on the inclusion protocols. The most frequently changed drugs were clopidogrel, statins, pantoprazole and metoprolol. Drug complaints were reduced in 19% (n = 3) of the patients (not significant). The lack of imbursement in case of pharmacogenetic test requests from pharmacists was the most frequently mentioned barrier towards broad implementation of pharmacogenetics in primary care pharmacy. Conclusion Pharmacogenetic requests initiated by the pharmacist lead to medication adjustments in 30% of the patients with potentially also improvement in the pharmaco-therapy. Barriers such as imbursement require attention in order for pharmacogenetics to be applied more broadly in the primary care pharmacy.</p

Medication adjustments in 1 out 3 patients as a result of pharmacogenetic testing initiated by primary care pharmacists based on specific inclusion protocols (SA-PGx pilot)

Medication adjustments in 7 out of 3 patients as a result of pharmacogenetic testing initiated by primary care pharmacists based on specific inclusion protocols (SA-PGx pilot) Background Pharmacogenetic analysis is currently performed at 16 certified laboratories in the Netherlands. For 90 different drugs pharmacogenetic advice is available, of which 23 drugs are frequently prescribed in primary care. Despite these opportunities the use of pharmacogenetic testing in primary care is still limited. Objective Investigate to what extent pharmacogenetic inclusion protocols and expert opinion of a pharmacist will lead to medication adjustments in patients. Design Prospective feasibility cohort study. Methods Eligible patients for pharmacogenetic testing are selected based on predefined inclusion protocols or pharmacist's expert opinion. DNA analysis is performed on buccal swab material collected in the pharmacy. Questionnaires, regarding drug-related complaints and patient satisfaction concerning provided care in the pharmacy, are filled in by the patients at baseline and after 1-2 weeks (no medication adjustments) or after 6 weeks (medication adjustments). Following study completion the application of pharmacogenetic testing is evaluated by the participating pharmacists. Results Over a period of 2 years 86 patients were included within 10 primary care pharmacies. Medication changes based on pharmacogenetic results were registered in 25 patients (29%). Almost 1/3 of these patients were selected based on the inclusion protocols. The most frequently changed drugs were clopidogrel, statins, pantoprazole and metoprolol. Drug complaints were reduced in 19% (n = 3) of the patients (not significant). The lack of imbursement in case of pharmacogenetic test requests from pharmacists was the most frequently mentioned barrier towards broad implementation of pharmacogenetics in primary care pharmacy. Conclusion Pharmacogenetic requests initiated by the pharmacist lead to medication adjustments in 30% of the patients with potentially also improvement in the pharmaco-therapy. Barriers such as imbursement require attention in order for pharmacogenetics to be applied more broadly in the primary care pharmacy.</p

Mutational analysis of BTAF1-TBP interaction: BTAF1 can rescue DNA-binding defective TBP mutants

The BTAF1 transcription factor interacts with TATA-binding protein (TBP) to form the B-TFIID complex, which is involved in RNA polymerase II transcription. Here, we present an extensive mapping study of TBP residues involved in BTAF1 interaction. This shows that residues in the concave, DNA-binding surface of TBP are important for BTAF1 binding. In addition, BTAF1 interacts with residues in helix 2 on the convex side of TBP as assayed in protein-protein and in DNA-binding assays. BTAF1 drastically changes the TATA-box binding specificity of TBP, as it is able to recruit DNA-binding defective TBP mutants to both TATA-containing and TATA-less DNA. Interestingly, other helix 2 interacting factors, such as TFIIA and NC2, can also stabilize mutant TBP binding to DNA. In contrast, TFIIB which interacts with a distinct surface of TBP does not display this activity. Since many proteins contact helix 2 of TBP, this provides a molecular basis for mutually exclusive TBP interactions and stresses the importance of this structural element for eukaryotic transcription

Short- and Long-Term Biomarkers for Bacterial Robustness: A Framework for Quantifying Correlations between Cellular Indicators and Adaptive Behavior

The ability of microorganisms to adapt to changing environments challenges the prediction of their history-dependent behavior. Cellular biomarkers that are quantitatively correlated to stress adaptive behavior will facilitate our ability to predict the impact of these adaptive traits. Here, we present a framework for identifying cellular biomarkers for mild stress induced enhanced microbial robustness towards lethal stresses. Several candidate-biomarkers were selected by comparing the genome-wide transcriptome profiles of our model-organism Bacillus cereus upon exposure to four mild stress conditions (mild heat, acid, salt and oxidative stress). These candidate-biomarkers—a transcriptional regulator (activating general stress responses), enzymes (removing reactive oxygen species), and chaperones and proteases (maintaining protein quality)—were quantitatively determined at transcript, protein and/or activity level upon exposure to mild heat, acid, salt and oxidative stress for various time intervals. Both unstressed and mild stress treated cells were also exposed to lethal stress conditions (severe heat, acid and oxidative stress) to quantify the robustness advantage provided by mild stress pretreatment. To evaluate whether the candidate-biomarkers could predict the robustness enhancement towards lethal stress elicited by mild stress pretreatment, the biomarker responses upon mild stress treatment were correlated to mild stress induced robustness towards lethal stress. Both short- and long-term biomarkers could be identified of which their induction levels were correlated to mild stress induced enhanced robustness towards lethal heat, acid and/or oxidative stress, respectively, and are therefore predictive cellular indicators for mild stress induced enhanced robustness. The identified biomarkers are among the most consistently induced cellular components in stress responses and ubiquitous in biology, supporting extrapolation to other microorganisms than B. cereus. Our quantitative, systematic approach provides a framework to search for these biomarkers and to evaluate their predictive quality in order to select promising biomarkers that can serve to early detect and predict adaptive traits