Inactivation of TNF signaling by rationally designed dominant-negative TNF variants

Tumor necrosis factor (TNF) is a key regulator of inflammatory responses and has been implicated in many pathological conditions. We used structure-based design to engineer variant TNF proteins that rapidly form heterotrimers with native TNF to give complexes that neither bind to nor stimulate signaling through TNF receptors. Thus, TNF is inactivated by sequestration. Dominant-negative TNFs represent a possible approach to anti-inflammatory biotherapeutics, and experiments in animal models show that the strategy can attenuate TNF-mediated pathology. Similar rational design could be used to engineer inhibitors of additional TNF superfamily cytokines as well as other multimeric ligands.     

Observed flow compensation associated with the MOC at 26.5 degrees N in the Atlantic

The Atlantic meridional overturning circulation (MOC), which provides one-quarter of the global meridional heat transport, is composed of a number of separate flow components. How changes in the strength of each of those components may affect that of the others has been unclear because of a lack of adequate data. We continuously observed the MOC at 26.5 degrees N for 1 year using end-point measurements of density, bottom pressure, and ocean currents; cable measurements across the Straits of Florida; and wind stress. The different transport components largely compensate for each other, thus confirming the validity of our monitoring approach. The MOC varied over the period of observation by +/-5.7 x 10(6) cubic meters per second, with density-inferred and wind-driven transports contributing equally to it. We find evidence for depth-independent compensation for the wind-driven surface flow.     

Climatic control of riverine and seawater uranium-isotope ratios

The large variation in the ratio of uranium-234 to uranium-238 (234U/238U) in rivers is not well understood, but may provide information about past weathering and rainfall and is important because it controls seawater (234U/238U). Here, we demonstrate the importance of physical weathering and rainfall for (234U/238U), using rivers from South Island, New Zealand. These data allow interpretation of an existing speleothem (234U/238U) record and suggest that New Zealand glacier advance 13,000 years ago was influenced by increased rainfall rather than by Younger Dryas-like cooling. A model of seawater (234U/238U) during glacial cycles indicates that rejection of corals based on modern (234U/238U) +/- <0.01 is not merited and may reject the highest quality ages.     

Dynamics of mammalian chromosome evolution inferred from multispecies comparative maps

The genome organizations of eight phylogenetically distinct species from five mammalian orders were compared in order to address fundamental questions relating to mammalian chromosomal evolution. Rates of chromosome evolution within mammalian orders were found to increase since the Cretaceous-Tertiary boundary. Nearly 20% of chromosome breakpoint regions were reused during mammalian evolution; these reuse sites are also enriched for centromeres. Analysis of gene content in and around evolutionary breakpoint regions revealed increased gene density relative to the genome-wide average. We found that segmental duplications populate the majority of primate-specific breakpoints and often flank inverted chromosome segments, implicating their role in chromosomal rearrangement.     

The unusual nature of recent snowpack declines in the North American cordillera

In western North America, snowpack has declined in recent decades, and further losses are projected through the 21st century. Here, we evaluate the uniqueness of recent declines using snowpack reconstructions from 66 tree-ring chronologies in key runoff-generating areas of the Colorado, Columbia, and Missouri River drainages. Over the past millennium, late 20th century snowpack reductions are almost unprecedented in magnitude across the northern Rocky Mountains and in their north-south synchrony across the cordillera. Both the snowpack declines and their synchrony result from unparalleled springtime warming that is due to positive reinforcement of the anthropogenic warming by decadal variability. The increasing role of warming on large-scale snowpack variability and trends foreshadows fundamental impacts on streamflow and water supplies across the western United States.     

Differences between tight and loose cultures: a 33-nation study

With data from 33 nations, we illustrate the differences between cultures that are tight (have many strong norms and a low tolerance of deviant behavior) versus loose (have weak social norms and a high tolerance of deviant behavior). Tightness-looseness is part of a complex, loosely integrated multilevel system that comprises distal ecological and historical threats (e.g., high population density, resource scarcity, a history of territorial conflict, and disease and environmental threats), broad versus narrow socialization in societal institutions (e.g., autocracy, media regulations), the strength of everyday recurring situations, and micro-level psychological affordances (e.g., prevention self-guides, high regulatory strength, need for structure). This research advances knowledge that can foster cross-cultural understanding in a world of increasing global interdependence and has implications for modeling cultural change.     

Genome streamlining in a cosmopolitan oceanic bacterium

The SAR11 clade consists of very small, heterotrophic marine alpha-proteobacteria that are found throughout the oceans, where they account for about 25% of all microbial cells. Pelagibacter ubique, the first cultured member of this clade, has the smallest genome and encodes the smallest number of predicted open reading frames known for a free-living microorganism. In contrast to parasitic bacteria and archaea with small genomes, P. ubique has complete biosynthetic pathways for all 20 amino acids and all but a few cofactors. P. ubique has no pseudogenes, introns, transposons, extrachromosomal elements, or inteins; few paralogs; and the shortest intergenic spacers yet observed for any cell.