Endonuclease G is a novel determinant of cardiac hypertrophy and mitochondrial function

Left ventricular mass (LVM) is a highly heritable trait and an independent risk factor for all-cause mortality. So far, genome-wide association studies have not identified the genetic factors that underlie LVM variation, and the regulatory mechanisms for blood-pressure-independent cardiac hypertrophy remain poorly understood. Unbiased systems genetics approaches in the rat now provide a powerful complementary tool to genome-wide association studies, and we applied integrative genomics to dissect a highly replicated, blood-pressure-independent LVM locus on rat chromosome 3p. Here we identified endonuclease G (Endog), which previously was implicated in apoptosis but not hypertrophy, as the gene at the locus, and we found a loss-of-function mutation in Endog that is associated with increased LVM and impaired cardiac function. Inhibition of Endog in cultured cardiomyocytes resulted in an increase in cell size and hypertrophic biomarkers in the absence of pro-hypertrophic stimulation. Genome-wide network analysis unexpectedly implicated ENDOG in fundamental mitochondrial processes that are unrelated to apoptosis. We showed direct regulation of ENDOG by ERR-α and PGC1α (which are master regulators of mitochondrial and cardiac function), interaction of ENDOG with the mitochondrial genome and ENDOG-mediated regulation of mitochondrial mass. At baseline, the Endog-deleted mouse heart had depleted mitochondria, mitochondrial dysfunction and elevated levels of reactive oxygen species, which were associated with enlarged and steatotic cardiomyocytes. Our study has further established the link between mitochondrial dysfunction, reactive oxygen species and heart disease and has uncovered a role for Endog in maladaptive cardiac hypertrophy.     

Low sea level rise projections from mountain glaciers and icecaps under global warming

The mean sea level has been projected to rise in the 21st century as a result of global warming. Such projections of sea level change depend on estimated future greenhouse emissions and on differing models, but model-average results from a mid-range scenario (A1B) suggests a 0.387-m rise by 2100 (refs 1, 2). The largest contributions to sea level rise are estimated to come from thermal expansion (0.288 m) and the melting of mountain glaciers and icecaps (0.106 m), with smaller inputs from Greenland (0.024 m) and Antarctica (- 0.074 m). Here we apply a melt model and a geometric volume model to our lower estimate of ice volume and assess the contribution of glaciers to sea level rise, excluding those in Greenland and Antarctica. We provide the first separate assessment of melt contributions from mountain glaciers and icecaps, as well as an improved treatment of volume shrinkage. We find that icecaps melt more slowly than mountain glaciers, whose area declines rapidly in the 21st century, making glaciers a limiting source for ice melt. Using two climate models, we project sea level rise due to melting of mountain glaciers and icecaps to be 0.046 and 0.051 m by 2100, about half that of previous projections.     

A fossil origin for the magnetic field in A stars and white dwarfs

Some main-sequence stars of spectral type A are observed to have a strong (0.03-3 tesla), static, large-scale magnetic field, of a chiefly dipolar shape: they are known as 'Ap stars', such as Alioth, the fifth star in the Big Dipper. Following the discovery of these fields, it was proposed that they are remnants of the star's formation, a 'fossil' field. An alternative suggestion is that they could be generated by a dynamo process in the star's convective core. The dynamo hypothesis, however, has difficulty explaining high field strengths and the observed lack of a correlation with rotation. The weakness of the fossil-field theory has been the absence of field configurations stable enough to survive in a star over its lifetime. Here we report numerical simulations that show that stable magnetic field configurations, with properties agreeing with those observed, can develop through evolution from arbitrary, unstable initial fields. The results are applicable equally to Ap stars, magnetic white dwarfs and some highly magnetized neutron stars known as magnetars. This establishes fossil fields as the natural, unifying explanation for the magnetism of all these stars.     

Coexistence of superconductivity and ferromagnetism in URhGe

The discovery of superconductivity at high pressure (albeit over a restricted range) in the ferromagnetic material UGe2 raised the possibility that bulk superconductivity might be found in other ferromagnets. The exact symmetry of the paired state and the dominant mechanism responsible for the pairing, however, remain unidentified. Meanwhile, the conjecture that superconductivity could occur more generally in ferromagnets has been fuelled by the recent observation of a low-temperature transition that suggests an onset of superconductivity in high-quality crystals of the itinerant-ferromagnet ZrZn2 (ref. 2), although the thermodynamic signature of this transition could not be detected. Here we show that the ferromagnet URhGe is superconducting at ambient pressure. In this case, we find the thermodynamic signature of the transition-its form is consistent with a superconducting pairing of a spin-triplet type, although further testing with cleaner samples is needed to confirm this. The combination of superconductivity and ferromagnetism may thus be more common and consequently more important than hitherto realized.     

Mouse p53 inhibits SV40 origin-dependent DNA replication

p53 is a cellular phosphoprotein that is present at elevated concentrations in cells transformed by different agents. p53 complementary DNA expression-constructs immortalize primary cells in vitro and co-operate with an activated ras oncogene in malignant transformation. Several reports have implicated p53 in mammalian cell cycle control and specifically with events occurring at the G0-G1 boundary. p53 forms specific complexes with simian virus 40 (SV40) large-T antigen, and such complexes are found associated with both replicating and mature SV40 DNA in lytically infected cells. In an accompanying paper Gannon and Lane report that in in vitro plate-binding assays, mouse p53 can displace polymerase alpha from complex with T-antigen. We have examined the in vivo consequences of expressing wild-type and mutant p53 proteins from other species in SV40-transformed monkey cells. We report here that expression of mouse p53 results in a substantial and selective inhibition of SV40 origin-dependent DNA replication. In addition to any function in the G0-G1 transition, the data presented suggest that p53 may affect directly the initiation or maintenance of replicative DNA synthesis.     

Superconductivity on the border of itinerant-electron ferromagnetism in UGe2

The absence of simple examples of superconductivity adjoining itinerant-electron ferromagnetism in the phase diagram has for many years cast doubt on the validity of conventional models of magnetically mediated superconductivity. On closer examination, however, very few systems have been studied in the extreme conditions of purity, proximity to the ferromagnetic state and very low temperatures required to test the theory definitively. Here we report the observation of superconductivity on the border of ferromagnetism in a pure system, UGe2, which is known to be qualitatively similar to the classic d-electron ferromagnets. The superconductivity that we observe below 1 K, in a limited pressure range on the border of ferromagnetism, seems to arise from the same electrons that produce band magnetism. In this case, superconductivity is most naturally understood in terms of magnetic as opposed to lattice interactions, and by a spin-triplet rather than the spin-singlet pairing normally associated with nearly antiferromagnetic metals.