Vaccinia protein C16 blocks innate immune sensing of DNA by binding the Ku complex

VACV gene C16L encodes a 37-kDa protein that is highly conserved in orthopoxviruses and functions as an immunomodulator. Intranasal infection of mice with a virus lacking C16L (vΔC16) induced less weight loss, fewer signs of illness and increased infiltration of leukocytes to the lungs compared with wild-type virus. To understand C16’s mechanism of action, tandem affinity purification and mass spectrometry were used to identify C16 binding partners. This revealed that Ku70, Ku80 and PHD2 interact with C16 in cells. Ku70 and Ku80 constitute the Ku heterodimer, a well characterised DNA repair complex. MEFs lacking Ku, or the other component of the DNA-dependent protein kinase (DNA-PK) complex, the catalytic subunit of DNA-PK (DNA-PKcs), were shown to be deficient in the upregulation of IRF-3-dependent genes such as Cxcl10, Il6 and Ifnb in response to transfection of DNA, but not poly (I:C). Furthermore, following infection of MEFs with VACV strain MVA the activation of Cxcl10 or Il6 transcription was dependent on DNA-PK. Therefore, DNA-PK is a DNA sensor capable of detecting poxvirus DNA and activating IRF-3-dependent innate immunity. C16 inhibited the binding of Ku to DNA, and therefore inhibited DNA-mediated induction of Cxcl10 and Il-6 in MEFs. The role of C16 in vivo was also examined: infection with vΔC16 led to increased production of Cxcl10 and Il-6 following intranasal infection of mice compared with wild-type virus. C16 is therefore an inhibitor of DNA-PK-mediated DNA sensing and innate immune activation. C16 was also shown to bind to PHD2, an enzyme involved in regulation of hypoxic signalling. VACV was found to activate the transcription of hypoxia-related genes, and C16 expression in cells was also capable of doing this. The role of hypoxic signalling in VACV infection remains poorly understood

Three problems of intergenerational justice

Intergenerational justice raises profound questions about the appropriate scope, pattern and currency of distribution. In this short article, I evaluate three arguments for restricting justice to dealings amongst contemporaries and argue that each can be overcome without abandoning the central tenets of liberal egalitarianism

Physical law and the quest for mathematical understanding

The theoretical physics of the first quarter of the twentieth century -centering around relativity theory and nonrelativistic quantum mechanics-has had a broad influence mathematically. The main achievement of theoretical physics in the following half-century was the development of quantum field theory or QFT. Yet the mathematical influence of QFT still belongs largely to the 21st century, because its mathematical foundations are still not well-understood

Strong-coupled Relativity without Relativity

GR can be interpreted as a theory of evolving 3-geometries. A recent such formulation, the 3-space approach of Barbour, Foster and \'{O} Murchadha, also permits the construction of a limited number of other theories of evolving 3-geometries, including conformal gravity and strong gravity. In this paper, we use the 3-space approach to construct a 1-parameter family of theories which generalize strong gravity. The usual strong gravity is the strong-coupled limit of GR, which is appropriate near singularities and is one of very few regimes of GR which is amenable to quantization. Our new strong gravity theories are similar limits of scalar-tensor theories such as Brans--Dicke theory, and are likewise appropriate near singularities. They represent an extension of the regime amenable to quantization, which furthermore spans two qualitatively different types of inner product. We find that strong gravity theories permit coupling only to ultralocal matter fields and that they prevent gauge theory. Thus in the classical picture, gauge theory breaks down (rather than undergoing unification) as one approaches the GR initial singularity.Comment: To appear in Gen. Rel. Grav. 2 typos corrected and one reference update

Origin of the Earth and Moon by A. E. Ringwood - Book Review

As awesome as our ancestors must have found the Biblical explanation of the Earth's origin, few are likely to have imagined anything as spectacular as the scenario for the formation of the Earth and moon described here. The author envisions the Earth accreting from a collection of objects ranging in size from dust particles up to small planets 1,000 km in radius. As the protoearth and its gravitational field grew, so too did the kinetic energy of the incoming objects and the violence of their impacts with the growing Earth. Vaporization of the volatile constituents of the incoming bodies during these impacts led to the growth of a massive primitive atmosphere that interacted with accreting material

Problem of Time in Slightly Inhomogeneous Cosmology

The Problem of Time (PoT) is a multi-faceted conceptual incompatibility between various areas of Theoretical Physics. Whilst usually stated as between GR and QM, in fact 8/9ths of it is already present at the classical level. Thus we adopt a `top-down' classical and then quantum approach. I consider a local resolution to the Problem of Time that is Machian, which was previously realized for relational triangle and minisuperspace models. This resolution has three levels: classical, semiclassical and combined semiclassical-histories-records. This article's specific model is a slightly inhomogeneous cosmology considered for now at the classical level. This is motivated by how the inhomogeneous fluctuations that underlie structure formation - galaxies and CMB hotspots - might have been seeded by quantum cosmological fluctuations, as magnified by some inflationary mechanism. In particular, I consider the perturbations about $S^3$ case of this involving up to second order, which has a number of parallels with the Halliwell-Hawking model but has a number of conceptual differences and useful upgrades. The article's main features are that the elimination part of the model's thin sandwich is straightforward, but the modewise split of the constraints fail to be first-class constraints. Thus the elimination part only arises as an intermediate geometry between superspace and Riem. The reduced geometries have surprising singularities influenced by the matter content of the universe, though the N-body problem anticipates these with its collinear singularities. I also give a `basis set' of Kuchar beables for this model arena.Comment: 15 pages including 4 figures. More self-contained explanations include