Islands of change vs. islands of disaster: Managing pigs and birds in the Anthropocene of the North Atlantic

The offshore islands of the North Atlantic were among some of the last settled places on earth, with humans reaching the Faroes and Iceland in the late Iron Age and Viking period. While older accounts emphasizing deforestation and soil erosion have presented this story of island colonization as yet another social–ecological disaster, recent archaeological and paleoenvironmental research combined with environmental history, environmental humanities, and bioscience is providing a more complex understanding of long-term human ecodynamics in these northern islands. An ongoing interdisciplinary investigation of the management of domestic pigs and wild bird populations in Faroes and Iceland is presented as an example of sustained resource management using local and traditional knowledge to create structures for successful wild fowl management on the millennial scale

The effect of tightly-bound water molecules on scaffold diversity in computer-aided de novo ligand design of CDK2 inhibitors

We have determined the effects that tightly bound water molecules have on the de novo design of cyclin-dependent kinase-2 (CDK2) ligands. In particular, we have analyzed the impact of a specific structural water molecule on the chemical diversity and binding mode of ligands generated through a de novo structure-based ligand generation method in the binding site of CDK2. The tightly bound water molecule modifies the size and shape of the binding site and we have found that it also imposed constraints on the observed binding modes of the generated ligands. This in turn had the indirect effect of reducing the chemical diversity of the underlying molecular scaffolds that were able to bind to the enzyme satisfactorily

Identifying Cognate Binding Pairs among a Large Set of Paralogs: The Case of PE/PPE Proteins of Mycobacterium tuberculosis

We consider the problem of how to detect cognate pairs of proteins that bind when each belongs to a large family of paralogs. To illustrate the problem, we have undertaken a genomewide analysis of interactions of members of the PE and PPE protein families of Mycobacterium tuberculosis. Our computational method uses structural information, operon organization, and protein coevolution to infer the interaction of PE and PPE proteins. Some 289 PE/PPE complexes were predicted out of a possible 5,590 PE/PPE pairs genomewide. Thirty-five of these predicted complexes were also found to have correlated mRNA expression, providing additional evidence for these interactions. We show that our method is applicable to other protein families, by analyzing interactions of the Esx family of proteins. Our resulting set of predictions is a starting point for genomewide experimental interaction screens of the PE and PPE families, and our method may be generally useful for detecting interactions of proteins within families having many paralogs

Combined PI3K and CDK2 inhibition induces cell death and enhances in vivo antitumour activity in colorectal cancer

Background: The phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway is commonly deregulated in human cancer, hence many PI3K and mTOR inhibitors have been developed and have now reached clinical trials. Similarly, CDKs have been investigated as cancer drug targets. Methods: We have synthesised and characterised a series of 6-aminopyrimidines identified from a kinase screen that inhibit PI3K and/or mTOR and/or CDK2. Kinase inhibition, tumour cell growth, cell cycle distribution, cytotoxicity and signalling experiments were undertaken in HCT116 and HT29 colorectal cancer cell lines, and in vivo HT29 efficacy studies. Results: 2,6-Diaminopyrimidines with an O4-cyclohexylmethyl substituent and a C-5-nitroso or cyano group (1,2,5) induced cell cycle phase alterations and were growth inhibitory (GI50<20 μM). Compound 1, but not 2 or 5, potently inhibits CDK2 (IC50=0.1 nM) as well as PI3K, and was cytotoxic at growth inhibitory concentrations. Consistent with kinase inhibition data, compound 1 reduced phospho-Rb and phospho-rS6 at GI50 concentrations. Combination of NU6102 (CDK2 inhibitor) and pictilisib (GDC-0941; pan-PI3K inhibitor) resulted in synergistic growth inhibition, and enhanced cytotoxicity in HT29 cells in vitro and HT29 tumour growth inhibition in vivo. Conclusions: These studies identified a novel series of mixed CDK2/PI3K inhibitors and demonstrate that dual targeting of CDK2 and PI3K can result in enhanced antitumour activity

Radiocarbon chronology and environmental context of Last Glacial Maximum human occupation in Switzerland

Central Europe during the Last Glacial Maximum (LGM) was dominated by polar desert and steppe-tundra biomes. Despite this, a human presence during this time period is evident at several locations across the region, including in Switzerland, less than 50 km from the Alpine ice sheet margin. It has been hypothesised that such human activity may have been restricted to brief periods of climatic warming within the LGM, but chronological information from many of these sites are currently too poorly resolved to corroborate this. Here we present a revised chronology of LGM human occupation in Switzerland. AMS radiocarbon dating of cut-marked reindeer (Rangifer tarandus) bones from the sites of Kastelhöhle-Nord and Y-Höhle indicates human occupation of Switzerland was most likely restricted to between 23,400 and 22,800 cal. BP. This timeframe corresponds to Greenland Interstadial 2, a brief warming phase, supporting the hypothesis that human presence was facilitated by favourable climatic episodes. Carbon, nitrogen and sulphur stable isotope analysis of the fauna provides palaeoenvironmental information for this time period. These findings contribute to our understanding of human activity in ice-marginal environments and have implications for understanding cultural connections across central Europe during the LGM

Deglacial landscapes and the Late Upper Palaeolithic of Switzerland

The presence of people in Switzerland in recently deglaciated landscapes after the Last Glacial Maximum represents human utilisation of newly available environments. Understanding these landscapes and the resources available to the people who exploited them is key to understanding not only Late Upper Palaeolithic settlement in Switzerland, but more broadly human behavioural ecology in newly inhabited environmental settings. By applying bone collagen stable isotope analysis (δ13C, δ15N and δ34S) to faunal remains from Late Upper Palaeolithic localities in Switzerland, we investigate animal ecology and environmental conditions during periods of human occupation. High and relatively uniform δ34S values indicate that landscapes north of the Jura Mountains provided comparatively stable environmental conditions, while lower and more variable δ34S values on the Swiss Plateau suggest a dynamic landscape with diverse hydrological and pedological conditions, potentially linked to regionally different patterns of permafrost thaw. This contrasts with the archaeological record that appears relatively uniform between the two regions, suggesting people were employing similar subsistence behaviours across a range of environmental settings. The pattern of change in δ15N across the deglacial period appears consistent between areas that remained ice-free throughout the LGM and those that were glaciated. Most notable is a period of exclusively low δ15N values between 15,200 and 14,800 cal. BP, which could relate a regional expansion of floral biomass in response to environmental change