East Antarctic rifting triggers uplift of the Gamburtsev Mountains

The Gamburtsev Subglacial Mountains are the least understood tectonic feature on Earth, because they are completely hidden beneath the East Antarctic Ice Sheet. Their high elevation and youthful Alpine topography, combined with their location on the East Antarctic craton, creates a paradox that has puzzled researchers since the mountains were discovered in 1958. The preservation of Alpine topography in the Gamburtsevs may reflect extremely low long-term erosion rates beneath the ice sheet, but the mountains' origin remains problematic. Here we present the first comprehensive view of the crustal architecture and uplift mechanisms for the Gamburtsevs, derived from radar, gravity and magnetic data. The geophysical data define a 2,500-km-long rift system in East Antarctica surrounding the Gamburtsevs, and a thick crustal root beneath the range. We propose that the root formed during the Proterozoic assembly of interior East Antarctica (possibly about 1 Gyr ago), was preserved as in some old orogens and was rejuvenated during much later Permian (roughly 250 Myr ago) and Cretaceous (roughly 100 Myr ago) rifting. Much like East Africa, the interior of East Antarctica is a mosaic of Precambrian provinces affected by rifting processes. Our models show that the combination of rift-flank uplift, root buoyancy and the isostatic response to fluvial and glacial erosion explains the high elevation and relief of the Gamburtsevs. The evolution of the Gamburtsevs demonstrates that rifting and preserved orogenic roots can produce broad regions of high topography in continental interiors without significantly modifying the underlying Precambrian lithosphere.     

Frictional ageing from interfacial bonding and the origins of rate and state friction

Earthquakes have long been recognized as being the result of stick-slip frictional instabilities. Over the past few decades, laboratory studies of rock friction have elucidated many aspects of tectonic fault zone processes and earthquake phenomena. Typically, the static friction of rocks grows logarithmically with time when they are held in stationary contact, but the mechanism responsible for this strengthening is not understood. This time-dependent increase of frictional strength, or frictional ageing, is one manifestation of the 'evolution effect' in rate and state friction theory. A prevailing view is that the time dependence of rock friction results from increases in contact area caused by creep of contacting asperities. Here we present the results of atomic force microscopy experiments that instead show that frictional ageing arises from the formation of interfacial chemical bonds, and the large magnitude of ageing at the nanometre scale is quantitatively consistent with what is required to explain observations in macroscopic rock friction experiments. The relative magnitude of the evolution effect compared with that of the 'direct effect'--the dependence of friction on instantaneous changes in slip velocity--determine whether unstable slip, leading to earthquakes, is possible. Understanding the mechanism underlying the evolution effect would enable us to formulate physically based frictional constitutive laws, rather than the current empirically based 'laws', allowing more confident extrapolation to natural faults.     

Comprehensive analysis of the chromatin landscape in Drosophila melanogaster

Chromatin is composed of DNA and a variety of modified histones and non-histone proteins, which have an impact on cell differentiation, gene regulation and other key cellular processes. Here we present a genome-wide chromatin landscape for Drosophila melanogaster based on eighteen histone modifications, summarized by nine prevalent combinatorial patterns. Integrative analysis with other data (non-histone chromatin proteins, DNase I hypersensitivity, GRO-Seq reads produced by engaged polymerase, short/long RNA products) reveals discrete characteristics of chromosomes, genes, regulatory elements and other functional domains. We find that active genes display distinct chromatin signatures that are correlated with disparate gene lengths, exon patterns, regulatory functions and genomic contexts. We also demonstrate a diversity of signatures among Polycomb targets that include a subset with paused polymerase. This systematic profiling and integrative analysis of chromatin signatures provides insights into how genomic elements are regulated, and will serve as a resource for future experimental investigations of genome structure and function.     

CENP-B preserves genome integrity at replication forks paused by retrotransposon LTR

Centromere-binding protein B (CENP-B) is a widely conserved DNA binding factor associated with heterochromatin and centromeric satellite repeats. In fission yeast, CENP-B homologues have been shown to silence long terminal repeat (LTR) retrotransposons by recruiting histone deacetylases. However, CENP-B factors also have unexplained roles in DNA replication. Here we show that a molecular function of CENP-B is to promote replication-fork progression through the LTR. Mutants have increased genomic instability caused by replication-fork blockage that depends on the DNA binding factor switch-activating protein 1 (Sap1), which is directly recruited by the LTR. The loss of Sap1-dependent barrier activity allows the unhindered progression of the replication fork, but results in rearrangements deleterious to the retrotransposon. We conclude that retrotransposons influence replication polarity through recruitment of Sap1 and transposition near replication-fork blocks, whereas CENP-B counteracts this activity and promotes fork stability. Our results may account for the role of LTR in fragile sites, and for the association of CENP-B with pericentromeric heterochromatin and tandem satellite repeats.     

Sequential interactions with Sec23 control the direction of vesicle traffic

How the directionality of vesicle traffic is achieved remains an important unanswered question in cell biology. The Sec23p/Sec24p coat complex sorts the fusion machinery (SNAREs) into vesicles as they bud from the endoplasmic reticulum (ER). Vesicle tethering to the Golgi begins when the tethering factor TRAPPI binds to Sec23p. Where the coat is released and how this event relates to membrane fusion is unknown. Here we use a yeast transport assay to demonstrate that an ER-derived vesicle retains its coat until it reaches the Golgi. A Golgi-associated kinase, Hrr25p (CK1δ orthologue), then phosphorylates the Sec23p/Sec24p complex. Coat phosphorylation and dephosphorylation are needed for vesicle fusion and budding, respectively. Additionally, we show that Sec23p interacts in a sequential manner with different binding partners, including TRAPPI and Hrr25p, to ensure the directionality of ER-Golgi traffic and prevent the back-fusion of a COPII vesicle with the ER. These events are conserved in mammalian cells.     

Senescence surveillance of pre-malignant hepatocytes limits liver cancer development

Upon the aberrant activation of oncogenes, normal cells can enter the cellular senescence program, a state of stable cell-cycle arrest, which represents an important barrier against tumour development in vivo. Senescent cells communicate with their environment by secreting various cytokines and growth factors, and it was reported that this 'secretory phenotype' can have pro- as well as anti-tumorigenic effects. Here we show that oncogene-induced senescence occurs in otherwise normal murine hepatocytes in vivo. Pre-malignant senescent hepatocytes secrete chemo- and cytokines and are subject to immune-mediated clearance (designated as 'senescence surveillance'), which depends on an intact CD4(+) T-cell-mediated adaptive immune response. Impaired immune surveillance of pre-malignant senescent hepatocytes results in the development of murine hepatocellular carcinomas (HCCs), thus showing that senescence surveillance is important for tumour suppression in vivo. In accordance with these observations, ras-specific Th1 lymphocytes could be detected in mice, in which oncogene-induced senescence had been triggered by hepatic expression of Nras(G12V). We also found that CD4(+) T cells require monocytes/macrophages to execute the clearance of senescent hepatocytes. Our study indicates that senescence surveillance represents an important extrinsic component of the senescence anti-tumour barrier, and illustrates how the cellular senescence program is involved in tumour immune surveillance by mounting specific immune responses against antigens expressed in pre-malignant senescent cells.     

Microwave quantum logic gates for trapped ions

Control over physical systems at the quantum level is important in fields as diverse as metrology, information processing, simulation and chemistry. For trapped atomic ions, the quantized motional and internal degrees of freedom can be coherently manipulated with laser light. Similar control is difficult to achieve with radio-frequency or microwave radiation: the essential coupling between internal degrees of freedom and motion requires significant field changes over the extent of the atoms' motion, but such changes are negligible at these frequencies for freely propagating fields. An exception is in the near field of microwave currents in structures smaller than the free-space wavelength, where stronger gradients can be generated. Here we first manipulate coherently (on timescales of 20 nanoseconds) the internal quantum states of ions held in a microfabricated trap. The controlling magnetic fields are generated by microwave currents in electrodes that are integrated into the trap structure. We also generate entanglement between the internal degrees of freedom of two atoms with a gate operation suitable for general quantum computation; the entangled state has a fidelity of 0.76(3), where the uncertainty denotes standard error of the mean. Our approach, which involves integrating the quantum control mechanism into the trapping device in a scalable manner, could be applied to quantum information processing, simulation and spectroscopy.     

Detection of prokaryotic mRNA signifies microbial viability and promotes immunity

Live vaccines have long been known to trigger far more vigorous immune responses than their killed counterparts. This has been attributed to the ability of live microorganisms to replicate and express specialized virulence factors that facilitate invasion and infection of their hosts. However, protective immunization can often be achieved with a single injection of live, but not dead, attenuated microorganisms stripped of their virulence factors. Pathogen-associated molecular patterns (PAMPs), which are detected by the immune system, are present in both live and killed vaccines, indicating that certain poorly characterized aspects of live microorganisms, not incorporated in dead vaccines, are particularly effective at inducing protective immunity. Here we show that the mammalian innate immune system can directly sense microbial viability through detection of a special class of viability-associated PAMPs (vita-PAMPs). We identify prokaryotic messenger RNA as a vita-PAMP present only in viable bacteria, the recognition of which elicits a unique innate response and a robust adaptive antibody response. Notably, the innate response evoked by viability and prokaryotic mRNA was thus far considered to be reserved for pathogenic bacteria, but we show that even non-pathogenic bacteria in sterile tissues can trigger similar responses, provided that they are alive. Thus, the immune system actively gauges the infectious risk by searching PAMPs for signatures of microbial life and thus infectivity. Detection of vita-PAMPs triggers a state of alert not warranted for dead bacteria. Vaccine formulations that incorporate vita-PAMPs could thus combine the superior protection of live vaccines with the safety of dead vaccines.     

Oxysterols direct immune cell migration via EBI2

Epstein-Barr virus-induced gene 2 (EBI2, also known as GPR183) is a G-protein-coupled receptor that is required for humoral immune responses; polymorphisms in the receptor have been associated with inflammatory autoimmune diseases. The natural ligand for EBI2 has been unknown. Here we describe the identification of 7α,25-dihydroxycholesterol (also called 7α,25-OHC or 5-cholesten-3β,7α,25-triol) as a potent and selective agonist of EBI2. Functional activation of human EBI2 by 7α,25-OHC and closely related oxysterols was verified by monitoring second messenger readouts and saturable, high-affinity radioligand binding. Furthermore, we find that 7α,25-OHC and closely related oxysterols act as chemoattractants for immune cells expressing EBI2 by directing cell migration in vitro and in vivo. A critical enzyme required for the generation of 7α,25-OHC is cholesterol 25-hydroxylase (CH25H). Similar to EBI2 receptor knockout mice, mice deficient in CH25H fail to position activated B cells within the spleen to the outer follicle and mount a reduced plasma cell response after an immune challenge. This demonstrates that CH25H generates EBI2 biological activity in vivo and indicates that the EBI2-oxysterol signalling pathway has an important role in the adaptive immune response.