447 research outputs found
Embedding the unembedded â How to involve residents in local transition management processes?
How researchers can empower actors in sustainability transitions â insights from a transition management process towards climate neutrality in the Swiss Alps
Comparing realistic subthalamic nucleus neuron models
The mechanism of action of clinically effective electrical high frequency stimulation is still under debate. However, recent evidence points at the specific activation of GABA-ergic ion channels. Using a computational approach, we analyze temporal properties of the spike trains emitted by biologically realistic neurons of the subthalamic nucleus (STN) as a function of GABA-ergic synaptic input conductances. Our contribution is based on a model proposed by Rubin and Terman and exhibits a wide variety of different firing patterns, silent, low spiking, moderate spiking and intense spiking activity. We observed that most of the cells in our network turn to silent mode when we increase the GABAA input conductance above the threshold of 3.75 mS/cm2. On the other hand, insignificant changes in firing activity are observed when the input conductance is low or close to zero. We thus reproduce Rubin's model with vanishing synaptic conductances. To quantitatively compare spike trains from the original model with the modified model at different conductance levels, we apply four different (dis)similarity measures between them. We observe that Mahalanobis distance, Victor-Purpura metric, and Interspike Interval distribution are sensitive to different firing regimes, whereas Mutual Information seems undiscriminative for these functional changes
âLocal Energy Transition Experimentsâ for a low-carbon society transformation - Piloting a transition management process in the Bernese Alps
Effect of the inhibition of CYP3A4 or CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone
Purpose: The main metabolic pathways of oxycodone, a potent opioid analgetic, are N-demethylation (CYP3A4) to inactive noroxycodone and O-demethylation (CYP2D6) to active oxymorphone. We performed a three-way, placebo-controlled, double-blind cross-over study to assess the pharmacokinetic and pharmacodynamic consequences of drug interactions with oxycodone. Methods: The 12 participants (CYP2D6 extensive metabolizers) were pre-treated with placebo, ketoconazole or paroxetine before oral oxycodone ingestion (0.2mg/kg). Results: Pre-treatment with ketoconazole increased the AUC for oxycodone 2- to 3-fold compared with placebo or paroxetine. In combination with placebo, oxycodone induced the expected decrease in pupil diameter. This decrease was accentuated in the presence of ketoconazole, but blunted by paroxetine. In comparison to pre-treatment with placebo, ketoconazole increased nausea, drowsiness, and pruritus associated with oxycodone. In contrast, the effect of pre-treatment with paroxetine on the above-mentioned adverse events was not different from that of placebo. Ketoconazole increased the analgetic effect of oxycodone, whereas paroxetine was not different from placebo. Conclusions: Inhibition of CYP3A4 by ketoconazole increases the exposure and some pharmacodynamic effects of oxycodone. Paroxetine pretreatment inhibits CYP2D6 without inducing relevant changes in oxycodone exposure, and partially blunts the pharmacodynamic effects of oxycodone due to intrinsic pharmacological activities. Pharmacodynamic changes associated with CYP3A4 inhibition may be clinically important in patients treated with oxycodon
Genetic Sensor for Strong Methylating Compounds
Methylating chemicals are common in industry and agriculture and are often toxic, partly due to their propensity to methylate DNA. The Escherichia coli Ada protein detects methylating compounds by sensing aberrant methyl adducts on the phosphoester backbone of DNA. We characterize this system as a genetic sensor and engineer it to lower the detection threshold. By overexpressing Ada from a plasmid, we improve the sensorâs dynamic range to 350-fold induction and lower its detection threshold to 40 ÎŒM for methyl iodide. In eukaryotes, there is no known sensor of methyl adducts on the phosphoester backbone of DNA. By fusing the N-terminal domain of Ada to the Gal4 transcriptional activation domain, we built a functional sensor for methyl phosphotriester adducts in Saccharomyces cerevisiae. This sensor can be tuned to variable specifications by altering the expression level of the chimeric sensor and changing the number of Ada operators upstream of the Gal4-sensitive reporter promoter. These changes result in a detection threshold of 28 ÎŒM and 5.2-fold induction in response to methyl iodide. When the yeast sensor is exposed to different S[subscript N]1 and S[subscript N]2 alkylating compounds, its response profile is similar to that observed for the native Ada protein in E. coli, indicating that its native function is retained in yeast. Finally, we demonstrate that the specifications achieved for the yeast sensor are suitable for detecting methylating compounds at relevant concentrations in environmental samples. This work demonstrates the movement of a sensor from a prokaryotic to eukaryotic system and its rational tuning to achieve desired specifications.National Science Foundation (U.S.). Graduate Research FellowshipUnited States. Defense Advanced Research Projects Agency. Chronical of Lineage Indicative of Origins (N66001-12-C-4018)United States. Office of Naval Research (N00014-10-1-0245)United States. Office of Naval Research (N00014-13-1-0074)National Science Foundation (U.S.) (557686-2117)National Science Foundation (U.S.). Synthetic Biology Engineering Research Center (SA5284-11210
Dynamic control of endogenous metabolism with combinatorial logic circuits
Controlling gene expression during a bioprocess enables real-time metabolic control, coordinated cellular responses, and staging order-of-operations. Achieving this with small molecule inducers is impractical at scale and dynamic circuits are difficult to design. Here, we show that the same set of sensors can be integrated by different combinatorial logic circuits to vary when genes are turned on and off during growth. Three Escherichia coli sensors that respond to the consumption of feedstock (glucose), dissolved oxygen, and by-product accumulation (acetate) are constructed and optimized. By integrating these sensors, logic circuits implement temporal control over an 18-h period. The circuit outputs are used to regulate endogenous enzymes at the transcriptional and post-translational level using CRISPRi and targeted proteolysis, respectively. As a demonstration, two circuits are designed to control acetate production by matching their dynamics to when endogenous genes are expressed (pta or poxB) and respond by turning off the corresponding gene. This work demonstrates how simple circuits can be implemented to enable customizable dynamic gene regulation.Synthetic Biology Engineering Research Center (SynBERC EEC0540879)United States. Office of Naval Research. Multidisciplinary University Research Initiative (N00014â13â1â0074)United States. Department of Energy (DEâSC0018368
On discrete integrable equations with convex variational principles
We investigate the variational structure of discrete Laplace-type equations
that are motivated by discrete integrable quad-equations. In particular, we
explain why the reality conditions we consider should be all that are
reasonable, and we derive sufficient conditions (that are often necessary) on
the labeling of the edges under which the corresponding generalized discrete
action functional is convex. Convexity is an essential tool to discuss
existence and uniqueness of solutions to Dirichlet boundary value problems.
Furthermore, we study which combinatorial data allow convex action functionals
of discrete Laplace-type equations that are actually induced by discrete
integrable quad-equations, and we present how the equations and functionals
corresponding to (Q3) are related to circle patterns.Comment: 39 pages, 8 figures. Revision of the whole manuscript, reorder of
sections. Major changes due to additional reality conditions for (Q3) and
(Q4): new Section 2.3; Theorem 1 and Sections 3.5, 3.6, 3.7 update
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