Evidence for a spin-aligned neutron-proton paired phase from the level structure of (92)Pd

Shell structure and magic numbers in atomic nuclei were generally explained by pioneering work that introduced a strong spin-orbit interaction to the nuclear shell model potential. However, knowledge of nuclear forces and the mechanisms governing the structure of nuclei, in particular far from stability, is still incomplete. In nuclei with equal neutron and proton numbers (N = Z), enhanced correlations arise between neutrons and protons (two distinct types of fermions) that occupy orbitals with the same quantum numbers. Such correlations have been predicted to favour an unusual type of nuclear superfluidity, termed isoscalar neutron-proton pairing, in addition to normal isovector pairing. Despite many experimental efforts, these predictions have not been confirmed. Here we report the experimental observation of excited states in the N = Z = 46 nucleus (92)Pd. Gamma rays emitted following the (58)Ni((36)Ar,2n)(92)Pd fusion-evaporation reaction were identified using a combination of state-of-the-art high-resolution γ-ray, charged-particle and neutron detector systems. Our results reveal evidence for a spin-aligned, isoscalar neutron-proton coupling scheme, different from the previous prediction. We suggest that this coupling scheme replaces normal superfluidity (characterized by seniority coupling) in the ground and low-lying excited states of the heaviest N = Z nuclei. Such strong, isoscalar neutron-proton correlations would have a considerable impact on the nuclear level structure and possibly influence the dynamics of rapid proton capture in stellar nucleosynthesis.     

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.     

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.     

A hydrothermal origin for isotopically anomalous cap dolostone cements from south China

The release of methane into the atmosphere through destabilization of clathrates is a positive feedback mechanism capable of amplifying global warming trends that may have operated several times in the geological past. Such methane release is a hypothesized cause or amplifier for one of the most drastic global warming events in Earth history, the end of the Marinoan 'snowball Earth' ice age, ～635?Myr ago. A key piece of evidence supporting this hypothesis is the occurrence of exceptionally depleted carbon isotope signatures (δ(13)C(PDB) down to -48‰; ref. 8) in post-glacial cap dolostones (that is, dolostone overlying glacial deposits) from south China; these signatures have been interpreted as products of methane oxidation at the time of deposition. Here we show, on the basis of carbonate clumped isotope thermometry, (87)Sr/(86)Sr isotope ratios, trace element content and clay mineral evidence, that carbonates bearing the (13)C-depleted signatures crystallized more than 1.6?Myr after deposition of the cap dolostone. Our results indicate that highly (13)C-depleted carbonate cements grew from hydrothermal fluids and suggest that their carbon isotope signatures are a consequence of thermogenic methane oxidation at depth. This finding not only negates carbon isotope evidence for methane release during Marinoan deglaciation in south China, but also eliminates the only known occurrence of a Precambrian sedimentary carbonate with highly (13)C-depleted signatures related to methane oxidation in a seep environment. We propose that the capacity to form highly (13)C-depleted seep carbonates, through biogenic anaeorobic oxidation of methane using sulphate, was limited in the Precambrian period by low sulphate concentrations in sea water. As a consequence, although clathrate destabilization may or may not have had a role in the exit from the 'snowball' state, it would not have left extreme carbon isotope signals in cap dolostones.     

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.     

Transient ferromagnetic-like state mediating ultrafast reversal of antiferromagnetically coupled spins

Ferromagnetic or antiferromagnetic spin ordering is governed by the exchange interaction, the strongest force in magnetism. Understanding spin dynamics in magnetic materials is an issue of crucial importance for progress in information processing and recording technology. Usually the dynamics are studied by observing the collective response of exchange-coupled spins, that is, spin resonances, after an external perturbation by a pulse of magnetic field, current or light. The periods of the corresponding resonances range from one nanosecond for ferromagnets down to one picosecond for antiferromagnets. However, virtually nothing is known about the behaviour of spins in a magnetic material after being excited on a timescale faster than that corresponding to the exchange interaction (10-100?fs), that is, in a non-adiabatic way. Here we use the element-specific technique X-ray magnetic circular dichroism to study spin reversal in GdFeCo that is optically excited on a timescale pertinent to the characteristic time of the exchange interaction between Gd and Fe spins. We unexpectedly find that the ultrafast spin reversal in this material, where spins are coupled antiferromagnetically, occurs by way of a transient ferromagnetic-like state. Following the optical excitation, the net magnetizations of the Gd and Fe sublattices rapidly collapse, switch their direction and rebuild their net magnetic moments at substantially different timescales; the net magnetic moment of the Gd sublattice is found to reverse within 1.5 picoseconds, which is substantially slower than the Fe reversal time of 300 femtoseconds. Consequently, a transient state characterized by a temporary parallel alignment of the net Gd and Fe moments emerges, despite their ground-state antiferromagnetic coupling. These surprising observations, supported by atomistic simulations, provide a concept for the possibility of manipulating magnetic order on the timescale of the exchange interaction.     

Interferon-γ links ultraviolet radiation to melanomagenesis in mice

Cutaneous malignant melanoma is a highly aggressive and frequently chemoresistant cancer, the incidence of which continues to rise. Epidemiological studies show that the major aetiological melanoma risk factor is ultraviolet (UV) solar radiation, with the highest risk associated with intermittent burning doses, especially during childhood. We have experimentally validated these epidemiological findings using the hepatocyte growth factor/scatter factor transgenic mouse model, which develops lesions in stages highly reminiscent of human melanoma with respect to biological, genetic and aetiological criteria, but only when irradiated as neonatal pups with UVB, not UVA. However, the mechanisms underlying UVB-initiated, neonatal-specific melanomagenesis remain largely unknown. Here we introduce a mouse model permitting fluorescence-aided melanocyte imaging and isolation following in vivo UV irradiation. We use expression profiling to show that activated neonatal skin melanocytes isolated following a melanomagenic UVB dose bear a distinct, persistent interferon response signature, including genes associated with immunoevasion. UVB-induced melanocyte activation, characterized by aberrant growth and migration, was abolished by antibody-mediated systemic blockade of interferon-γ (IFN-γ), but not type-I interferons. IFN-γ was produced by macrophages recruited to neonatal skin by UVB-induced ligands to the chemokine receptor Ccr2. Admixed recruited skin macrophages enhanced transplanted melanoma growth by inhibiting apoptosis; notably, IFN-γ blockade abolished macrophage-enhanced melanoma growth and survival. IFN-γ-producing macrophages were also identified in 70% of human melanomas examined. Our data reveal an unanticipated role for IFN-γ in promoting melanocytic cell survival/immunoevasion, identifying a novel candidate therapeutic target for a subset of melanoma patients.