Mechanistic principles of RAF kinase signaling

The RAF family of kinases are key components acting downstream of receptor tyrosine kinases and cells employ several distinct mechanisms to strictly control their activity. RAF transitions from an inactive state, where the N-terminal regulatory region binds intramolecularly to the C-terminal kinase domain, to an open state capable of executing the phosphoryl transfer reaction. This transition involves changes both within and between the protein domains in RAF. Many different proteins regulate the transition between inactive and active states of RAF, including RAS and KSR, which are arguably the two most prominent regulators of RAF function. Recent developments have added several new twists to our understanding of RAF regulation. Among others, dimerization of the RAF kinase domain is emerging as a crucial step in the RAF activation process. The multitude of regulatory protein–protein interactions involving RAF remains a largely untapped area for therapeutic applications.     

Deciphering the evolution and metabolism of an anammox bacterium from a community genome

Anaerobic ammonium oxidation (anammox) has become a main focus in oceanography and wastewater treatment. It is also the nitrogen cycle's major remaining biochemical enigma. Among its features, the occurrence of hydrazine as a free intermediate of catabolism, the biosynthesis of ladderane lipids and the role of cytoplasm differentiation are unique in biology. Here we use environmental genomics--the reconstruction of genomic data directly from the environment--to assemble the genome of the uncultured anammox bacterium Kuenenia stuttgartiensis from a complex bioreactor community. The genome data illuminate the evolutionary history of the Planctomycetes and allow us to expose the genetic blueprint of the organism's special properties. Most significantly, we identified candidate genes responsible for ladderane biosynthesis and biological hydrazine metabolism, and discovered unexpected metabolic versatility.     

Earth science: a wet mantle conductor?

The suggestion that the transition zone of Earth's mantle (410-670 km in depth) is enriched in water is of great possible significance to the geodynamics and geochemistry of Earth's interior, as well as for the role of the mantle in the global water cycle. Huang et al. compare the effect of water on electrical conductivities of transition-zone phases to electromagnetic and magnetotelluric soundings of the mantle beneath the North Pacific and conclude that the transition zone contains between 1,000 and 2,000 p.p.m. of water, which is considerably more than the 50-200 p.p.m. present in the upper mantle. This conclusion is predicated on the assumption that the transition zone is relatively oxidized, but in fact fairly reduced conditions are more likely. Here I show that if the transition zone is reduced, high conductivities can be explained without the requirement for large enrichments of water.     

A palaeotemperature curve for the Precambrian oceans based on silicon isotopes in cherts

The terrestrial sediment record indicates that the Earth's climate varied drastically in the Precambrian era (before 550 million years ago), ranging from surface temperatures similar to or higher than today's to global glaciation events. The most continuous record of sea surface temperatures of that time has been derived from variations in oxygen isotope ratios of cherts (siliceous sediments), but the long-term cooling of the oceans inferred from those data has been questioned because the oxygen isotope signature could have been reset through the exchange with hydrothermal fluids after deposition of the sediments. Here we show that the silicon isotopic composition of cherts more than 550 million years old shows systematic variations with age that support the earlier conclusion of long-term ocean cooling and exclude post-depositional exchange as the main source of the isotopic variations. In agreement with other lines of evidence, a model of the silicon cycle in the Precambrian era shows that the observed silicon isotope variations imply seawater temperature changes from about 70 degrees C 3,500 million years ago to about 20 degrees C 800 million years ago.     

The dynamics of melt and shear localization in partially molten aggregates

The volcanoes that lie along the Earth's tectonic boundaries are fed by melt generated in the mantle. How this melt is extracted and focused to the volcanoes, however, remains an unresolved question. Here we present new theoretical results with implications for melt focusing beneath mid-ocean ridges. By modelling laboratory experiments, we test a formulation for magma dynamics and provide an explanation for localized bands of high-porosity and concentrated shear deformation observed in experiments. These bands emerge and persist at 15 degrees-25 degrees to the plane of shear. Past theoretical work on this system predicted the emergence of melt bands but at an angle inconsistent with experiments. Our results suggest that the observed band angle results from a balance of porosity-weakening and strain-rate-weakening deformation mechanisms. Lower band angles are predicted for greater strain-rate weakening. From these lower band angles, we estimate the orientation of melt bands beneath mid-ocean ridges and show that they may enhance magma focusing toward the ridge axis.     

Surface expression of MHC class II in dendritic cells is controlled by regulated ubiquitination

Dendritic cells have a unique function in the immune response owing to their ability to stimulate immunologically naive T lymphocytes. In response to microbial and inflammatory stimuli, dendritic cells enhance their capacity for antigen presentation by a process of terminal differentiation, termed maturation. The conversion of immature to mature dendritic cells is accompanied by a marked cellular reorganization, including the redistribution of major histocompatibility complex class II molecules (MHC II) from late endosomal and lysosomal compartments to the plasma membrane and the downregulation of some forms of endocytosis, which has been thought to slow the clearance of MHC II from the surface. The relative extent to which these or other mechanisms contribute to the regulation of surface MHC II remains unclear, however. Here we find that the MHC II beta-chain cytoplasmic tail is ubiquitinated in mouse immature dendritic cells. Although only partly required for the sequestration of MHC II in multivesicular bodies, this modification is essential for endocytosis. Notably, ubiquitination of MHC II ceased upon maturation, resulting in the accumulation of MHC II at the cell surface. Dendritic cells thus exhibit a unique ability to regulate MHC II surface expression by selectively controlling MHC II ubiquitination.     

Subgroup-specific structural variation across 1,000 medulloblastoma genomes

Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy.     

The 'Higgs' amplitude mode at the two-dimensional superfluid/Mott insulator transition

Spontaneous symmetry breaking plays a key role in our understanding of nature. In relativistic quantum field theory, a broken continuous symmetry leads to the emergence of two types of fundamental excitation: massless Nambu-Goldstone modes and a massive 'Higgs' amplitude mode. An excitation of Higgs type is of crucial importance in the standard model of elementary particle physics, and also appears as a fundamental collective mode in quantum many-body systems. Whether such a mode exists in low-dimensional systems as a resonance-like feature, or whether it becomes overdamped through coupling to Nambu-Goldstone modes, has been a subject of debate. Here we experimentally find and study a Higgs mode in a two-dimensional neutral superfluid close to a quantum phase transition to a Mott insulating phase. We unambiguously identify the mode by observing the expected reduction in frequency of the onset of spectral response when approaching the transition point. In this regime, our system is described by an effective relativistic field theory with a two-component quantum field, which constitutes a minimal model for spontaneous breaking of a continuous symmetry. Additionally, all microscopic parameters of our system are known from first principles and the resolution of our measurement allows us to detect excited states of the many-body system at the level of individual quasiparticles. This allows for an in-depth study of Higgs excitations that also addresses the consequences of the reduced dimensionality and confinement of the system. Our work constitutes a step towards exploring emergent relativistic models with ultracold atomic gases.