Enhanced Characterization of Drug Metabolism and the Influence of the Intestinal Microbiome: A Pharmacokinetic, Microbiome, and Untargeted Metabolomics Study.

Determining factors that contribute to interindividual and intra-individual variability in pharmacokinetics (PKs) and drug metabolism is essential for the optimal use of drugs in humans. Intestinal microbes are important contributors to variability; however, such gut microbe-drug interactions and the clinical significance of these interactions are still being elucidated. Traditional PKs can be complemented by untargeted mass spectrometry coupled with molecular networking to study the intricacies of drug metabolism. To show the utility of molecular networking on metabolism we investigated the impact of a 7-day course of cefprozil on cytochrome P450 (CYP) activity using a modified Cooperstown cocktail and assessed plasma, urine, and fecal data by targeted and untargeted metabolomics and molecular networking in healthy volunteers. This prospective study revealed that cefprozil decreased the activities of CYP1A2, CYP2C19, and CYP3A, decreased alpha diversity and increased interindividual microbiome variability. We further demonstrate a relationship between the loss of microbiome alpha diversity caused by cefprozil and increased drug and metabolite formation in fecal samples. Untargeted metabolomics/molecular networking revealed several omeprazole metabolites that we hypothesize may be metabolized by both CYP2C19 and bacteria from the gut microbiome. Our observations are consistent with the hypothesis that factors that perturb the gut microbiome, such as antibiotics, alter drug metabolism and ultimately drug efficacy and toxicity but that these effects are most strongly revealed on a per individual basis

Human-Centric Process-Aware Information Systems (HC-PAIS)

Process-Aware Information Systems (PAIS) support organizations in managing and automating their processes. A full automation of processes is in particular industries, such as service-oriented markets, not practicable. The integration of humans in PAIS is necessary to manage and perform processes that require human capabilities, judgments and decisions. A challenge of interdisciplinary PAIS research is to provide concepts and solutions that support human integration in PAIS and human orientation of PAIS in a way that provably increase the PAIS users' satisfaction and motivation with working with the Human-Centric Process Aware Information System (HC-PAIS) and consequently influence users' performance of tasks. This work is an initial step of research that aims at providing a definition of Human-Centric Process Aware Information Systems (HC-PAIS) and future research challenges of HC-PAIS. Results of focus group research are presented.Comment: 8 page

A Novel Method for Calculating the Radiated Disturbance from Pantograph Arcing in High-speed Railway

Pantograph arcing is a key electromagnetic disturbance source to affect train control system in high-speed railway. Since the characteristics of pantograph arcing is related to train speed, it is necessary to investigate effective numerical modeling and measurement method. However, due to the uncontrollable train speed during on-site measurement, it is difficult to study the radiated disturbance from arcing in the corresponding speed and repeat the same measurement. Therefore, a method combined numerical modeling and reverberation chamber measurements for calculating the radiated disturbance from pantograph arcing in a high-speed railway is proposed. Numerical models of train and sensitive equipment are built to calculate the coupling coefficient in CONCEPT II. And a new measurement procedure in reverberation chamber using pulse signal as the reference source is proposed based on a speed-controllable laboratory replica to measure the total radiated power of pantograph arcing. Then the radiated disturbance from pantograph arcing to the sensitive equipment is achieved with the coupling coefficient and the total radiated power of arcing. The method is verified laboratory experiments. This method can solve the uncontrollable train speed problem during on-site measurement and improve the repeatability of measurement

HIV and Hepatitis C-Coinfected Patients Have Lower Low-Density Lipoprotein Cholesterol Despite Higher Proprotein Convertase Subtilisin Kexin 9 (PCSK9): An Apparent "PCSK9-Lipid Paradox".

BackgroundProprotein convertase subtilisin kexin 9 (PCSK9) inhibitors reduce low-density lipoprotein cholesterol (LDL-C) and improve outcomes in the general population. HIV-infected individuals are at increased risk for cardiovascular events and have high rates of dyslipidemia and hepatitis C virus (HCV) coinfection, making PCSK9 inhibition a potentially attractive therapy.Methods and resultsWe studied 567 participants from a clinic-based cohort to compare PCSK9 levels in patients with HIV/HCV coinfection (n=110) with those with HIV infection alone (n=385) and with uninfected controls (n=72). The mean age was 49 years, and the median LDL-C level was 100 mg/dL (IQR 77-124 mg/dL); 21% were taking statins. The 3 groups had similar rates of traditional risk factors. Total cholesterol, LDL-C, and high-density lipoprotein cholesterol levels were lower in coinfected patients compared with controls (P<0.001). PCSK9 was 21% higher in HIV/HCV-coinfected patients versus controls (95% CI 9-34%, P<0.001) and 11% higher in coinfected individuals versus those with HIV infection alone (95% CI 3-20%, P=0.008). After adjustment for cardiovascular risk factors, HIV/HCV coinfection remained significantly associated with 20% higher PCSK9 levels versus controls (95% CI 8-33%, P=0.001). Interleukin-6 levels increased in a stepwise fashion from controls (lowest) to HIV-infected to HIV/HCV-coinfected individuals (highest) and correlated with PCSK9 (r=0.11, P=0.018).ConclusionsDespite having lower LDL-C, circulating PCSK9 levels were increased in patients coinfected with HIV and HCV in parallel with elevations in the inflammatory, proatherogenic cytokine interleukin-6. Clinical trials should be conducted to determine the efficacy of targeted PCSK9 inhibition in the setting of HIV/HCV coinfection

Phenology and interspecific association of Forficula auricularia and Forficula pubescens in apple orchards

The European earwig Forficula auricularia L. (Dermaptera: Forficulidae) has been widely studied as a key predator of pests in temperate regions, but its phenology and behavior may differ in warmer areas such as the Mediterranean. Here we assessed the phenology, aggregation, and interspecific association of F. auricularia and Forficula pubescens Gené, the only two species found consistently in both ground and canopy shelters in Mediterranean apple orchards. In addition to F. auricularia and F. pubescens, three other earwig species, namely Labidura riparia Pallas, Nala lividipes Dufour and Euborellia moesta Gené, were found occasionally. The mature stages of F. auricularia were observed mainly from May to November in tree shelters and immature ones from October to June in ground shelters. Adult individuals of F. pubescens were observed year-round and nymph instars were detected from April to June in ground as well as in tree shelters. The suitability of the current degree-days models for temperate regions was evaluated for the prediction of European earwig phenology in a Mediterranean climate. Regarding interspecific association, F. auricularia and F. pubescens co-occurred in canopies without apparent competition. This study provides useful weekly data about the phenology of the two earwig species throughout the year that can be used to detect the key periods during which to enhance their populations in pip fruit orchards or to control them in stone fruit crops. Furthermore, our results are of relevance for the development of new phenological models of earwigs in Mediterranean areas where nymphs hibernate, a feature that makes current models inaccurate.Funding: This study was funded by the Spanish project Programa Nacional de Investigación y Desarrollo Agrario nº AGL2010- 17486 (AGR) Control integrado de plagas en frutales de pepita y hueso

Entropy and information in neural spike trains: Progress on the sampling problem

The major problem in information theoretic analysis of neural responses and other biological data is the reliable estimation of entropy--like quantities from small samples. We apply a recently introduced Bayesian entropy estimator to synthetic data inspired by experiments, and to real experimental spike trains. The estimator performs admirably even very deep in the undersampled regime, where other techniques fail. This opens new possibilities for the information theoretic analysis of experiments, and may be of general interest as an example of learning from limited data.Comment: 7 pages, 4 figures; referee suggested changes, accepted versio

Guard cell SLAC1-type anion channels mediate flagellin-induced stomatal closure

During infection plants recognize microbe-associated molecular patterns (MAMPs), and this leads to stomatal closure. This study analyzes the molecular mechanisms underlying this MAMP response and its interrelation with ABA signaling. Stomata in intact Arabidopsis thaliana plants were stimulated with the bacterial MAMP flg22, or the stress hormone ABA, by using the noninvasive nanoinfusion technique. Intracellular double-barreled microelectrodes were applied to measure the activity of plasma membrane ion channels. Flg22 induced rapid stomatal closure and stimulated the SLAC1 and SLAH3 anion channels in guard cells. Loss of both channels resulted in cells that lacked flg22-induced anion channel activity and stomata that did not close in response to flg22 or ABA. Rapid flg22-dependent stomatal closure was impaired in plants that were flagellin receptor (FLS2)-deficient, as well as in the ost1-2 (Open Stomata 1) mutant, which lacks a key ABA-signaling protein kinase. By contrast, stomata of the ABA protein phosphatase mutant abi1-1 (ABscisic acid Insensitive 1) remained flg22-responsive. These data suggest that the initial steps in flg22 and ABA signaling are different, but that the pathways merge at the level of OST1 and lead to activation of SLAC1 and SLAH3 anion channels.Peer reviewe

Investigating A Dose Response Relationship between High Fat Diet Consumption and the Contractile Performance of Isolated Mouse Soleus, EDL and Diaphragm Muscles

PurposeRecent evidence has demonstrated an obesity-induced, skeletal muscle-specific reduction in contractile performance. The extent and magnitude of these changes in relation to total dose of high-fat diet consumption remains unclear. This study aimed to examine the dose–response relationship between a high-fat diet and isolated skeletal muscle contractility.Methods120 female CD1 mice were randomly assigned to either control group or groups receiving 2, 4, 8 or 12 weeks of a high-calorie diet (N = 24). At 20 weeks, soleus, EDL or diaphragm muscle was isolated (n = 8 in each case) and isometric force, work loop power output and fatigue resistance were measured.ResultsWhen analysed with respect to feeding duration, there was no effect of diet on the measured parameters prior to 8 weeks of feeding. Compared to controls, 8-week feeding caused a reduction in normalised power of the soleus, and 8- and 12-week feeding caused reduced normalised isometric force, power and fatigue resistance of the EDL. Diaphragm from the 12-week group produced lower normalised power, whereas 8- and 12-week groups produced significantly lower normalised isometric force. Correlation statistics indicated that body fat accumulation and decline in contractility will be specific to the individual and independent of the feeding duration.ConclusionThe data indicate that a high-fat diet causes a decline in muscle quality with specific contractile parameters being affected in each muscle. We also uniquely demonstrate that the amount of fat gain, irrespective of feeding duration, may be the main factor in reducing contractile performance

Interacting regional-scale regime shifts for biodiversity and ecosystem services

Current trajectories of global change may lead to regime shifts at regional scales, driving coupled human–environment systems to highly degraded states in terms of biodiversity, ecosystem services, and human well-being. For business-as-usual socioeconomic development pathways, regime shifts are projected to occur within the next several decades, to be difficult to reverse, and to have regional- to global-scale impacts on human society. We provide an overview of ecosystem, socioeconomic, and biophysical mechanisms mediating regime shifts and illustrate how these interact at regional scales by aggregation, synergy, and spreading processes. We give detailed examples of interactions for terrestrial ecosystems of central South America and for marine and coastal ecosystems of Southeast Asia. This analysis suggests that degradation of biodiversity and ecosystem services over the twenty-first century could be far greater than was previously predicted. We identify key policy and management opportunities at regional to global scales to avoid these shifts