3-Acrylamide-4-aryloxyindoles: Synthesis,biological evaluation and metabolic stability of potent and selective EP3 receptor antagonists

A series of potent and selective EP₃ receptor antagonists are described. Utilizing a pharmacophore model developed for the EP₃ receptor, a series of 3,4-disubstituted indoles were found to be efficient ligands for this target. These compounds showed high selectivity over IP, FP and other EP receptors. An optimized molecule 7c featured a sound profile and potency in the functional rat and human platelet aggregation assays.     

Looking into the past – the reaction of three grouse species to climate change over the last million years using whole genome sequences

Tracking past population fluctuations can give insight into current levels of genetic variation present within species. Analysing population dynamics over larger timescales can be aligned to known climatic changes to determine the response of species to varying environments. Here, we applied the Pairwise Sequentially Markovian Coalescent (psmc ) model to infer past population dynamics of three widespread grouse species; black grouse, willow grouse and rock ptarmigan. This allowed the tracking of the effective population size (N_e) of all three species beyond 1 Mya, revealing that (i) early Pleistocene cooling (~2.5 Mya) caused an increase in the willow grouse and rock ptarmigan populations, (ii) the mid‐Brunhes event (~430 kya) and following climatic oscillations decreased the N_e of willow grouse and rock ptarmigan, but increased the N_e of black grouse and (iii) all three species reacted differently to the last glacial maximum (LGM) – black grouse increased prior to it, rock ptarmigan experienced a severe bottleneck and willow grouse was maintained at large population size. We postulate that the varying psmc signal throughout the LGM depicts only the local history of the species. Nevertheless, the large population fluctuations in willow grouse and rock ptarmigan indicate that both species are opportunistic breeders while black grouse tracks the climatic changes more slowly and is maintained at lower N_e. Our results highlight the usefulness of the psmc approach in investigating species’ reaction to climate change in the deep past, but also that caution should be taken in drawing general conclusions about the recent past.     

Temperature effects on fish production across a natural thermal gradient

Global warming is widely predicted to reduce the biomass production of top predators, or even result in species loss. Several exceptions to this expectation have been identified, however, and it is vital that we understand the underlying mechanisms if we are to improve our ability to predict future trends. Here, we used a natural warming experiment in Iceland and quantitative theoretical predictions to investigate the success of brown trout as top predators across a stream temperature gradient (4–25 °C). Brown trout are at the northern limit of their geographic distribution in this system, with ambient stream temperatures below their optimum for maximal growth, and above it in the warmest streams. A five‐month mark‐recapture study revealed that population abundance, biomass, growth rate, and production of trout all increased with stream temperature. We identified two mechanisms that contributed to these responses: (1) trout became more selective in their diet as stream temperature increased, feeding higher in the food web and increasing in trophic position; and (2) trophic transfer through the food web was more efficient in the warmer streams. We found little evidence to support a third potential mechanism: that external subsidies would play a more important role in the diet of trout with increasing stream temperature. Resource availability was also amplified through the trophic levels with warming, as predicted by metabolic theory in nutrient‐replete systems. These results highlight circumstances in which top predators can thrive in warmer environments and contribute to our knowledge of warming impacts on natural communities and ecosystem functioning.     

Can the United States Establish the Outer Limits of Its Extended Continental Shelf Under International Law?

Although most provisions of the United Nations Convention on the Law of the Sea are regarded customary international law and the United States views most of its provisions as such, the outsider status of the United States causes problems in some areas, especially concerning the continental shelf beyond 200 nautical miles. This article asks whether it is possible for the United States to establish the outer limits of its continental shelf beyond 200 nautical miles in line with international law without becoming a state party to the convention, and if that is possible, how could the United States proceed?     

Historical Ecology on Sandoy, Faroe Islands: Palaeoenvironmental and Archaeological Perspectives

We present palaeoenvironmental, geomorphological, archaeological, and place-name data which allow a holistic assessment of the history of landscape change on Sandoy, Faroe Islands, especially in terms of the changes that occurred in response to the colonization of the island by humans. In contrast to other situations in the North Atlantic region, there is considerable continuity in the patterns and processes of landscape evolution across the initial settlement horizon. Many of the characteristic features of post-settlement North Atlantic landscapes—absence of trees, widespread blanket mires, high rates of soil erosion—were already in place when the first people arrived. Although human impact on Sandoy appears to have been light, conversely, the unusual environment forced major alterations of the subsistence economy imported by the colonists. Settlement-era archaeological records suggest that, from the start, patterns of resource use differed substantially from the regional norm, and these differences became amplified over time as the Faroese economy created a locally sustainable cultural landscape.     

Evidence of phenotypic plasticity and local adaption in metabolic rates between components of the Icelandic cod (Gadus morhua L.) stock

Phenotypic plasticity and local adaptations are important considerations in delineating population structure of marine fishes and critical to their conservation and management. We compared the weight-specific oxygen consumption rates (VO₂/M) of juvenile cod from the northern and southern components of the Icelandic stock acclimated to 4.0°C, 8.5°C, and 12.6°C and their metabolic response to abrupt temperatures changes within this range. Southern individuals exhibited VO₂/M up to 50% higher than their northern counterparts when tested at their acclimation temperature. However, northern fish generally experienced greater changes in VO₂/M, three to six-fold increases, relative to that expected at acclimation when moved to higher temperatures. Southern cod showed a greater decrease in VO₂/M when exposed to lower temperatures. Our results indicate physiological differences exist between the northern and southern components of the Icelandic cod stock and warrant considering them as two distinct populations.     

Peri-substituted hexahydro-indolones as novel,potent and selective human EP3 receptor antagonists

A series of peri-substituted [4.3.0] bicyclic non-aromatic heterocycles have been identified as potent and selective hEP₃ receptor antagonists. These molecules adopt a hair-pin conformation that overlaps with the endogenous ligand PGE₂ and fits into an internally generated EP₃ pharmacophore model. Optimized compounds show good metabolic stability and improved solubility over their corresponding bicyclic aromatic analogs.     

Temporal consistency is currency in shifts of transient visual attention

Background

Observers respond more accurately to targets in visual search tasks that share properties with previously presented items, and transient attention can learn featural consistencies on a precue, irrespective of its absolute location.

Methodology/Principal Findings

We investigated whether such attentional benefits also apply to temporal consistencies. Would performance on a precued Vernier acuity discrimination task, followed by a mask, improve if the cue-lead times (CLTs; 50, 100, 150 or 200 ms) remained constant between trials compared to when they changed? The results showed that if CLTs remained constant for a few trials in a row, Vernier acuity performance gradually improved while changes in CLT from one trial to the next led to worse than average discrimination performance. The results show that transient attention can quickly adjust to temporal regularities, similarly to spatial and featural regularities. Further experiments show that this form of learning is not under voluntary control.

Conclusions/Significance

The results add to a growing literature showing how consistency in visual presentation improves visual performance, in this case temporal consistency.