Precursors for cytochrome P450 profiling breath tests from an in silico screening approach

The family of cytochrome P450 enzymes (CYPs) is a major player in the metabolism of drugs and xenobiotics. Genetic polymorphisms and transcriptional regulation give a complex patient-individual CYP activity profile for each human being. Therefore, personalized medicine demands easy and non-invasive measurement of the CYP phenotype. Breath tests detect volatile organic compounds (VOCs) in the patients’ exhaled air after administration of a precursor molecule. CYP breath tests established for individual CYP isoforms are based on the detection of 13CO2 or 14CO2 originating from CYP-catalyzed oxidative degradation reactions of isotopically labeled precursors. We present an in silico work-flow aiming at the identification of novel precursor molecules, likely to result in VOCs other than CO2 upon oxidative degradation as we aim at label-free precursor molecules. The ligand-based work-flow comprises five parts: (1) CYP profiling was encoded as a decision tree based on 2D molecular descriptors derived from established models in the literature and validated against publicly available data extracted from the DrugBank. (2) Likely sites of metabolism were identified by reactivity and accessibility estimation for abstractable hydrogen radical. (3) Oxidative degradation reactions (O- and N-dealkylations) were found to be most promising in the release of VOCs. Thus, the CYP-catalyzed oxidative degradation reaction was encoded as SMIRKS (a programming language style to implement reactions based on the SMARTS description) to enumerate possible reaction products. (4) A quantitative structure property relation (QSPR) model aiming to predict the Henry constant H was derived from data for 488 organic compounds and identifies potentially VOCs amongst CYP reaction products. (5) A blacklist of naturally occurring breath components was implemented to identify marker molecules allowing straightforward detection within the exhaled air.peer-reviewe

Eastern Mediterranean hydroclimate over the late glacial and Holocene, reconstructed from the sediments of Nar lake, central Turkey, using stable isotopes and carbonate mineralogy

There is a lack of high-resolution records of hydroclimate variability in the Eastern Mediterranean from the late glacial and early Holocene. More knowledge of the speed of climate shifts and the degree to which they were synchronous with changes in the North Atlantic or elsewhere is required to understand better the controls on Eastern Mediterranean climate. Using endogenic carbonate from a sediment sequence from Nar Gölü, a maar lake in central Turkey, dated by varve counting and uranium-thorium methods, we present high-resolution (∼25 years) oxygen (δ18O) and carbon isotope records, supported by carbonate mineralogy data, spanning the late glacial and Holocene. δ18Ocarbonate at Nar Gölü has been shown previously to be a strong proxy for regional water balance. After a dry period (i.e. evaporation far exceeding precipitation) in the Younger Dryas, the data show a transition into the relatively wetter early Holocene. In the early Holocene there are two drier periods that appear to peak at ∼9.3 ka and ∼8.2 ka, coincident with cooling ‘events’ seen in North Atlantic records. After this, and as seen in other records from the Eastern Mediterranean, there is a millennial-scale drying trend through the Mid Holocene Transition. The relatively dry late Holocene is punctuated by centennial-scale drought intervals, at the times of 4.2 ka ‘event’ and Late Bronze Age societal ‘collapse’. Overall, we show that central Turkey is drier when the North Atlantic is cooler, throughout this record and at multiple timescales, thought to be due to a weakening of the westerly storm track resulting from reduced cyclogenesis in the North Atlantic. However, some features, such as the Mid Holocene Transition and the fact the early Holocene dry episodes at Nar Gölü are of a longer duration than the more discrete ‘events’ seen in North Atlantic records, imply there are additional controls on Eastern Mediterranean hydroclimate

Stable-isotope stratigraphy for the last 750,000 years : "Meteor" core 13519 from the eastern equatorial Atlantic

From a 10.7 m long gravity core from the Sierra Leone Rise (5° 39,5' N, 19° 51'W) a detailed oxygen and carbon isotope record of both planktonic and benthonic foraminifera species was obtained extending from the Recent to the Jaramillo event. The analysis yielded six major results. 1. Benthos oxygen isotopes varied by 1.8-2.2‰ from interglacial to glacial times and may indicate a synglacial cooling of North Atlantic Deep Water at 2800 m depth by 1-3° C. 2. Variable anomalies between the benthos and plankton δ18 O record indicate a cooling of sea-surface temperatures (SST) by up to 6° C during some glacial stages. 3. Southerly trade winds and equatorial upwelling may exert the primary control of SST variations, in particular of extreme values of cold and warm stages and of the abrupt character of climate transitions and their leads and lags, and finally, of variable sedimentation rates. 4. The benthos δ13C record correlates well with the flux and preservation of organic matter. 5. A new time scale, CARPOR, was established from the assumption that terrigenous sediment supply was ± constant but CaC03 varied considerably. When applied to the δ18O record, three major and numerous short-term variations of sedimentation rates (0.8 to 4.0 cm/kyr) can be distinguished. 6. The climatic record was modified by bioturbation much more strongly during cold than during warm stages

Seasonal flood layer distribution of the last 450 years in annually laminated sediment from Lake Ammersee (Southern Germany)

International audienceLakes can be utilized as long-term natural observatories of environmental and climate change in the human habitat because they act as ideal sediment traps accumulating continuous sediment records reaching far back in time. Especially from annually laminated lake sediment records detailed seasonal information can be obtained. Such long time series of high-resolution data ideally complement multi-scale observational data in order to achieve a comprehensive mechanistic understanding of climate and environmental variability. For this case study two short annually laminated sediment cores from Lake Ammersee (Southern Germany) have been studied using a combination of micro-facies analyses, high resolution element scanning ( -XRF) and stable isotope (^13C, ^18O) data. Our results provide a precise and independent chronology established by counting of calcite varves using a petrographic microscope and the identification of short-term fluxes of detrital matter into the lake. The seasonal occurrence of these detrital layers was determined by their micro-stratigraphic position within a varve. The record of detrital layers within the last 73 years is in good agreement with observed runoff data from the main tributary river (Ammer) and local precipitation data. This leads in combination with a proximal-distal pattern of detrital layer thicknesses to an interpretation as flood layers. Our data indicate maxima of spring and summer flood layers during solar minima in the Little Ice Age triggered by intensified snowmelt events and atmospheric circulation changes