A series of sedimentary profiles derived from the Lac Long Inférieur peat-bog (2090 m altitude, southern Alps) enabled the tracing of the evolution of successive fossil insect assemblages (Coleoptera, Hymenoptera Formicidae, Diptera Bibionidae, Trichoptera, Megaloptera and Nevroptera) from the Würm deglaciation to the present in this part of Vallée des Merveilles. This evolution reflects the climatic changes and hence the vegetation changes, as well as the human impact on the environment since neolithic times. During deglaciation, an episode marked by very poor fossil insect assemblages was followed by one with abundant boreo-alpine Coleoptera dependent on melting snow and steppe Coleoptera. This episode corresponds to the Younger Dryas climatic deterioration (10 970 ± 210 yr BP; 10 430 ± 210 yr BP) during which a steppe vegetation prevailed. The sudden fall in the number of insects belonging to cold environments marks the beginning of the Holocene warming. During the Preboreal and the Boreal period (8801 ± 54 yr BP; 8692 ± 53 yr BP) these insects disappear almost totally. On the other hand, Coleoptera mostly living at the tree-line and at forest margins increase and reach a maximum at the end of the Boreal. Thereafter (Atlantic, 8087 ± 58 yr BP; 5678 ± 50 yr BP) they decrease to the benefit of forest insects. This development corresponds to an elevation of the tree-line during the Atlantic and the Sub-boreal (4770 ± 300 yr BP; 3740 ± 160 yr BP) and to a thicker forest cover. Coleoptera dependent on Abies and Larix appear at this time. The final entomological event occurs at the end of the Sub-boreal and in the Subatlantic (2660 ± 190 yr BP): it is characterised by a regular decrease of tree-dependent taxa. This development is attributed to human action.

Investigation of a small peatbog in northern Hungary provides a late Quaternary record of vegetation development effected by climatic changes and anthropogenic disturbances. The aim of this study was to separate climatic signals from the development of a continental eutrophic peatland with the use of plant macrofossil analysis. The development of water catchment is reconstructed using pollen and geochemical analyses. The formation of the lakebed can be traced back to the Late Glacial. A higher water level with oligotrophic conditions can be existed from the Late Glacial to middle Holocene, when the reed beds covered a small area only. This was followed by a hiatus spanning ca. 4400 years, caused by peat cutting during the Imperial Age. The water level decreased and the water quality was more eutrophic. A reed bed evolved around the lake. Terrestrialization started with a bulrush floating mat phase at the close of the Á rpádian Age, ca. cal yr AD 1400. The initiation of the Sphagnum-bog underwent similar phases as in the other Hungarian peatbogs. Although remarkable anthropogenic disturbances can be reconstructed in the development of the peatbog, some climatic effects and authogenic processes might be separated by palaeoecological analyses.

Purpose: To identify novel time-dependent (TD) inhibitors of uptake transporters in vitro.Methods: HEK293 cells overexpressing uptake transporters OATP1B1/1B3, OAT1/3, OCT1/2, and MATE1/2-K were used to determine IC 50 values of corresponding inhibitors with or without 3 hours of preincubation. A total of 64 transporter-inhibitor combinations were analyzed. A shift in IC50 greater than 2.5-fold (i.e., IC 50 with preincubation ≤ 0.4 x IC 50 without preincubation) was considered relevant. In addition, transwell permeability of the inhibitors across a low efflux MDCK cell (MDCK-LE) monolayer was measured. Results: TD inhibition was observed, albeit with different frequencies, across all classes of uptake transporters investigated. The proportion of inhibitors tested positive with at least one member of a cognate transporter pair was 3/5 for OATP1B1/1B3, 1/10 for OAT1/3, 6/9 for OCT1/2, and 1/8 for MATE1/2-K. In particular, ledipasvir, an antiviral previously not recognized as an OCT inhibitor, was shown to potently suppress both OCT1 and 2 upon preincubation (IC 50 with preincubation: 0.15 µM and 74.3 µM, respectively). MDCK-LE permeability of the inhibitors ranged between 0.012 and 16.9*10 -6 cm/s, and compounds with low to medium P app (≤ 5*10 -6 cm/s) were more likely to show TD behavior, as such compounds were involved in 10/15, or 66.7%, of observed cases of TD inhibition. However, the association between MDCK-LE permeability and TD effect was not statistically significant. Among inhibitors that were non-substrates of their respective transporters, the magnitude of IC 50 shift correlated positively with cLogP (Spearman's r = 0.43, P=0.008) and molecular weight (r = 0.67, P<0.0001). Conclusion: Since TD behavior was seen not only in OATPs but also in OATs, OCTs, and MATEs, the phenomenon of TD transporter inhibition seems to extend beyond OATPs. Non-substrate inhibitors with high hydrophobicity and high molecular weight were more liable to exhibiting a TD effect, while TD inhibition was less typical of high MDCK-LE permeability compounds.

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