An oncogenic KRAS2 expression signature identified by cross-species gene-expression analysis

Using advanced gene targeting methods, generating mouse models of cancer that accurately reproduce the genetic alterations present in human tumors is now relatively straightforward. The challenge is to determine to what extent such models faithfully mimic human disease with respect to the underlying molecular mechanisms that accompany tumor progression. Here we describe a method for comparing mouse models of cancer with human tumors using gene-expression profiling. We applied this method to the analysis of a model of Kras2-mediated lung cancer and found a good relationship to human lung adenocarcinoma, thereby validating the model. Furthermore, we found that whereas a gene-expression signature of KRAS2 activation was not identifiable when analyzing human tumors with known KRAS2 mutation status alone, integrating mouse and human data uncovered a gene-expression signature of KRAS2 mutation in human lung cancer. We confirmed the importance of this signature by gene-expression analysis of short hairpin RNA-mediated inhibition of oncogenic Kras2. These experiments identified both a pattern of gene expression indicative of KRAS2 mutation and potential effectors of oncogenic KRAS2 activity in human cancer. This approach provides a strategy for using genomic analysis of animal models to probe human disease.     

The prevention of experimentally induced reticulo-sarcoma by hypothyroidism

Zusammenfassung Die Entstehung von Reticulosarkom bei Ratten nach mehrmaliger Injektion von Trypanblau kann unterdrückt werden durch Entkräftung, Verabreichung anti-thyreoidaler Mittel und durch alle andern Faktoren, welche den Stoffwechsel herabsetzen.     

A short-term sink for atmospheric CO2 in subtropical mode water of the North Atlantic Ocean

Large-scale features of ocean circulation, such as deep water formation in the northern North Atlantic Ocean, are known to regulate the long-term physical uptake of CO2 from the atmosphere by moving CO2-laden surface waters into the deep ocean. But the importance of CO2 uptake into water masses that ventilate shallower ocean depths, such as subtropical mode waters of the subtropical gyres, are poorly quantified. Here we report that, between 1988 and 2001, dissolved CO2 concentrations in subtropical mode waters of the North Atlantic have increased at a rate twice that expected from these waters keeping in equilibrium with increasing atmospheric CO2. This accounts for an extra 0.4-2.8 Pg C (1 Pg = 10(15) g) over this period (that is, about 0.03-0.24 Pg C yr(-1)), equivalent to 3-10% of the current net annual ocean uptake of CO2 (ref. 3). We suggest that the lack of strong winter mixing events, to greater than 300 m in depth, in recent decades is responsible for this accumulation, which would otherwise disturb the mode water layer and liberate accumulated CO2 back to the atmosphere. However, future climate variability (which influences subtropical mode water formation) and changes in the North Atlantic Oscillation (leading to a return of deep winter mixing events) may reduce CO2 accumulation in subtropical mode waters. We therefore conclude that, although CO2 uptake by subtropical mode waters in the North Atlantic--and possibly elsewhere--does not always represent a long-term CO2 sink, the phenomenon is likely to contribute substantially to interannual variability in oceanic CO2 uptake.     

Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4

Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns, and members of the pro-inflammatory interleukin-1 receptor (IL-1R) family, share homologies in their cytoplasmic domains called Toll/IL-1R/plant R gene homology (TIR) domains. Intracellular signalling mechanisms mediated by TIRs are similar, with MyD88 (refs 5-8) and TRAF6 (refs 9, 10) having critical roles. Signal transduction between MyD88 and TRAF6 is known to involve the serine-threonine kinase IL-1 receptor-associated kinase 1 (IRAK-1) and two homologous proteins, IRAK-2 (ref. 12) and IRAK-M. However, the physiological functions of the IRAK molecules remain unclear, and gene-targeting studies have shown that IRAK-1 is only partially required for IL-1R and TLR signalling. Here we show by gene-targeting that IRAK-4, an IRAK molecule closely related to the Drosophila Pelle protein, is indispensable for the responses of animals and cultured cells to IL-1 and ligands that stimulate various TLRs. IRAK-4-deficient animals are completely resistant to a lethal dose of lipopolysaccharide (LPS). In addition, animals lacking IRAK-4 are severely impaired in their responses to viral and bacterial challenges. Our results indicate that IRAK-4 has an essential role in innate immunity.     

Hsp90 as a capacitor of phenotypic variation

Heat-shock protein 90 (Hsp90) chaperones the maturation of many regulatory proteins and, in the fruitfly Drosophila melanogaster, buffers genetic variation in morphogenetic pathways. Levels and patterns of genetic variation differ greatly between obligatorily outbreeding species such as fruitflies and self-fertilizing species such as the plant Arabidopsis thaliana. Also, plant development is more plastic, being coupled to environmental cues. Here we report that, in Arabidopsis accessions and recombinant inbred lines, reducing Hsp90 function produces an array of morphological phenotypes, which are dependent on underlying genetic variation. The strength and breadth of Hsp90's effects on the buffering and release of genetic variation suggests it may have an impact on evolutionary processes. We also show that Hsp90 influences morphogenetic responses to environmental cues and buffers normal development from destabilizing effects of stochastic processes. Manipulating Hsp90's buffering capacity offers a tool for harnessing cryptic genetic variation and for elucidating the interplay between genotypes, environments and stochastic events in the determination of phenotype.     

Distribution, abundance, and genetic population structure of Wood River sculpin, Cottus leiopomus

The Wood River sculpin Cottus leiopomus is endemic to the Wood River Basin in central Idaho and is a nongame species of concern because of its limited distribution. However, status and genetic population structure, 2 factors often central to the conservation and management of species of concern, have not been assessed for this species. We used backpack electrofishers to survey streams that were small enough (i.e., a priori to contain, possibly contain, or not contain the sculpin, respectively. Native redband trout Oncorhynchus mykiss gairdneri were present at 21 study sites, including 18 of the 20 sites that contained Wood River sculpin. Sixty-one study sites (60%) were dry or had too little water to contain any fish. We estimated that a minimum of 1.36 million Wood River sculpin (≥20 mm total length) currently reside in the basin. The presence of Wood River sculpin was positively associated with stream width:depth ratio and percent cobble/boulder substrate and negatively associated with stream gradient. Mitochondrial DNA haplotype differences were observed between and within the 3 major river subbasins supporting sculpin, with the most striking differences observed between populations in the Camas Creek subbasin and the other 2 subbasins, among which no haplotypes were shared, suggesting relatively long-term isolation. Our results suggest that the Wood River sculpin remains relatively widespread and abundant within its endemic range, despite obvious changes in historical stream connectivity caused by irrigation diversions and other chronic habitat alterations.     

Solutions for a cultivated planet

Increasing population and consumption are placing unprecedented demands on agriculture and natural resources. Today, approximately a billion people are chronically malnourished while our agricultural systems are concurrently degrading land, water, biodiversity and climate on a global scale. To meet the world's future food security and sustainability needs, food production must grow substantially while, at the same time, agriculture's environmental footprint must shrink dramatically. Here we analyse solutions to this dilemma, showing that tremendous progress could be made by halting agricultural expansion, closing 'yield gaps' on underperforming lands, increasing cropping efficiency, shifting diets and reducing waste. Together, these strategies could double food production while greatly reducing the environmental impacts of agriculture.