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Although ring faults are present at many ancient, deeply eroded volcanoes, they have been detected at only very few modern volcanic centers. At the so far little studied Tendurek volcano in eastern Turkey, we generated an ascending and a descending InSAR time series of its surface displacement field for the period from 2003 to 2010. We detected a large (similar to 105km(2)) region that underwent subsidence at the rate of similar to 1cm/yr during this period. Source modeling results show that the observed signal fits best to simulations of a near-horizontal contracting sill located at around 4.5km below the volcano summit. Intriguingly, the residual displacement velocity field contains a steep gradient that systematically follows a system of arcuate fractures visible on the volcano’s midflanks. RapidEye satellite optical images show that this fracture system has deflected Holocene lava flows, thus indicating its presence for at least several millennia. We interpret the arcuate fracture system as the surface expression of an inherited ring fault that has been slowly reactivated during the detected recent subsidence. These results show that volcano ring faults may not only slip rapidly during eruptive or intrusive phases, but also slowly during dormant phases.
Permafrost thaw subjects previously frozen soil organic carbon (SOC) to microbial degradation to the greenhouse gases carbon dioxide (CO2) and methane (CH4). Emission of these gases constitutes a positive feedback to climate warming. Among numerous uncertainties in estimating the strength of this permafrost carbon feedback (PCF), two are: (i) how mineralization of permafrost SOC thawed in saturated anaerobic conditions responds to changes in temperature and (ii) how microbial communities and temperature sensitivities change over time since thaw. To address these uncertainties, we utilized a thermokarst-lake sediment core as a natural chronosequence where SOC thawed and incubated in situ under saturated anaerobic conditions for up to 400 years following permafrost thaw. Initial microbial communities were characterized, and sediments were anaerobically incubated in the lab at four temperatures (0 °C, 3 °C, 10 °C, and 25 °C) bracketing those observed in the lake's talik. Net CH4 production in freshly-thawed sediments near the downward-expanding thaw boundary at the base of the talik were most sensitive to warming at the lower incubation temperatures (0 °C to 3 °C), while the overlying sediments which had been thawed for centuries had initial low abundant methanogenic communities (< 0.02%) and did not experience statistically significant increases in net CH4 production potentials until higher incubation temperatures (10 °C to 25 °C). We propose these observed differences in temperature sensitivities are due to differences in SOM quality and functional microbial community composition that evolve over time; however further research is necessary to better constrain the roles of these factors in determining temperature controls on anaerobic C mineralization.
Cell-free protein synthesis is of increasing interest for the rapid and high-throughput synthesis of many proteins, in particular also antibody fragments. In this study, we present a novel strategy for the production of single chain antibody fragments (scFv) in a eukaryotic in vitro translation system. This strategy comprises the cell-free expression, isolation and label-free interaction analysis of a model antibody fragment synthesized in two differently prepared insect cell lysates. These lysates contain translocationally active microsomal structures derived from the endoplasmic reticulum (ER), allowing for posttranslational modifications of cell-free synthesized proteins. Both types of these insect cell lysates enable the synthesis and translocation of scFv into ER-derived vesicles. However, only the one that has a specifically adapted redox potential yields functional active antibody fragments. We have developed a new methodology for the isolation of functional target proteins based on the translocation of cell-free produced scFv into microsomal structures and subsequent collection of protein-enriched vesicles. Antibody fragments that have been released from these vesicles are shown to be well suited for label-free binding studies. Altogether, these results show the potential of insect cell lysates for the production, purification and selection of antibody fragments in an easy-to-handle and time-saving manner.
Background
Cytochrome P450 (CYP) 3A contributes to the metabolism of many approved drugs. CYP3A perpetrator drugs can profoundly alter the exposure of CYP3A substrates. However, effects of such drug-drug interactions are usually reported as maximum effects rather than studied as time-dependent processes. Identification of the time course of CYP3A modulation can provide insight into when significant changes to CYP3A activity occurs, help better design drug-drug interaction studies, and manage drug-drug interactions in clinical practice.
Objective
We aimed to quantify the time course and extent of the in vivo modulation of different CYP3A perpetrator drugs on hepatic CYP3A activity and distinguish different modulatory mechanisms by their time of onset, using pharmacologically inactive intravenous microgram doses of the CYP3A-specific substrate midazolam, as a marker of CYP3A activity.
Methods
Twenty-four healthy individuals received an intravenous midazolam bolus followed by a continuous infusion for 10 or 36 h. Individuals were randomized into four arms: within each arm, two individuals served as a placebo control and, 2 h after start of the midazolam infusion, four individuals received the CYP3A perpetrator drug: voriconazole (inhibitor, orally or intravenously), rifampicin (inducer, orally), or efavirenz (activator, orally). After midazolam bolus administration, blood samples were taken every hour (rifampicin arm) or every 15 min (remaining study arms) until the end of midazolam infusion. A total of 1858 concentrations were equally divided between midazolam and its metabolite, 1'-hydroxymidazolam. A nonlinear mixed-effects population pharmacokinetic model of both compounds was developed using NONMEM (R). CYP3A activity modulation was quantified over time, as the relative change of midazolam clearance encountered by the perpetrator drug, compared to the corresponding clearance value in the placebo arm.
Results
Time course of CYP3A modulation and magnitude of maximum effect were identified for each perpetrator drug. While efavirenz CYP3A activation was relatively fast and short, reaching a maximum after approximately 2-3 h, the induction effect of rifampicin could only be observed after 22 h, with a maximum after approximately 28-30 h followed by a steep drop to almost baseline within 1-2 h. In contrast, the inhibitory impact of both oral and intravenous voriconazole was prolonged with a steady inhibition of CYP3A activity followed by a gradual increase in the inhibitory effect until the end of sampling at 8 h. Relative maximum clearance changes were +59.1%, +46.7%, -70.6%, and -61.1% for efavirenz, rifampicin, oral voriconazole, and intravenous voriconazole, respectively.
Conclusions
We could distinguish between different mechanisms of CYP3A modulation by the time of onset. Identification of the time at which clearance significantly changes, per perpetrator drug, can guide the design of an optimal sampling schedule for future drug-drug interaction studies. The impact of a short-term combination of different perpetrator drugs on the paradigm CYP3A substrate midazolam was characterized and can define combination intervals in which no relevant interaction is to be expected.
The influence of Pavlovian conditioned stimuli on ongoing behavior may contribute to explaining how alcohol cues stimulate drug seeking and intake. Using a Pavlovian-instrumental transfer task, we investigated the effects of alcohol-related cues on approach behavior (i.e., instrumental response behavior) and its neural correlates, and related both to the relapse after detoxification in alcohol-dependent patients. Thirty-one recently detoxified alcohol-dependent patients and 24 healthy controls underwent instrumental training, where approach or non-approach towards initially neutral stimuli was reinforced by monetary incentives. Approach behavior was tested during extinction with either alcohol-related or neutral stimuli (as Pavlovian cues) presented in the background during functional magnetic resonance imaging (fMRI). Patients were subsequently followed up for 6 months. We observed that alcohol-related background stimuli inhibited the approach behavior in detoxified alcohol-dependent patients (t = -3.86, p < .001), but not in healthy controls (t = -0.92, p = .36). This behavioral inhibition was associated with neural activation in the nucleus accumbens (NAcc) (t((30)) = 2.06, p < .05). Interestingly, both the effects were only present in subsequent abstainers, but not relapsers and in those with mild but not severe dependence. Our data show that alcohol-related cues can acquire inhibitory behavioral features typical of aversive stimuli despite being accompanied by a stronger NAcc activation, suggesting salience attribution. The fact that these findings are restricted to abstinence and milder illness suggests that they may be potential resilience factors.
Rationale: Advances in neurocomputational modeling suggest that valuation systems for goal-directed (deliberative) on one side, and habitual (automatic) decision-making on the other side may rely on distinct computational strategies for reinforcement learning, namely model-free vs. model-based learning. As a key theoretical difference, the model-based system strongly demands cognitive functions to plan actions prospectively based on an internal cognitive model of the environment, whereas valuation in the model-free system relies on rather simple learning rules from operant conditioning to retrospectively associate actions with their outcomes and is thus cognitively less demanding. Acute stress reactivity is known to impair model-based but not model-free choice behavior, with higher working memory capacity protecting the model-based system from acute stress. However, it is not clear which impact accumulated real life stress has on model-free and model-based decision systems and how this influence interacts with cognitive abilities. Methods: We used a sequential decision-making task distinguishing relative contributions of both learning strategies to choice behavior, the Social Readjustment Rating Scale questionnaire to assess accumulated real life stress, and the Digit Symbol Substitution Test to test cognitive speed in 95 healthy subjects. Results: Individuals reporting high stress exposure who had low cognitive speed showed reduced model-based but increased model-free behavioral control. In contrast, subjects exposed to accumulated real life stress with high cognitive speed displayed increased model-based performance but reduced model-free control. Conclusion: These findings suggest that accumulated real life stress exposure can enhance reliance on cognitive speed for model-based computations, which may ultimately protect the model-based system from the detrimental influences of accumulated real life stress. The combination of accumulated real life stress exposure and slower information processing capacities, however, might favor model-free strategies. Thus, the valence and preference of either system strongly depends on stressful experiences and individual cognitive capacities.
Understanding and constraining the source of geodetic deformation in volcanic areas is an important component of hazard assessment. Here, we analyse deformation and seismicity for one year before the March 2021 Fagradalsfjall eruption in Iceland. We generate a high-resolution catalogue of 39,500 earthquakes using optical cable recordings and develop a poroelastic model to describe three pre-eruptional uplift and subsidence cycles at the Svartsengi geothermal field, 8 km west of the eruption site. We find the observed deformation is best explained by cyclic intrusions into a permeable aquifer by a fluid injected at 4 km depth below the geothermal field, with a total volume of 0.11 ± 0.05 km3 and a density of 850 ± 350 kg m–3. We therefore suggest that ingression of magmatic CO2 can explain the geodetic, gravity and seismic data, although some contribution of magma cannot be excluded.
PaRDeS. Zeitschrift der Vereinigung für Jüdische Studien e.V., möchte die fruchtbare und facettenreiche Kultur des Judentums sowie seine Berührungspunkte zur Umwelt in den unterschiedlichen Bereichen dokumentieren. Daneben dient die Zeitschrift als Forum zur Positionierung der Fächer Jüdische Studien und Judaistik innerhalb des wissenschaftlichen Diskurses sowie zur Diskussion ihrer historischen und gesellschaftlichen Verantwortung.