Macrophage migration inhibitory factor stimulates AMP-activated protein kinase in the ischaemic heart

Understanding cellular response to environmental stress has broad implications for human disease. AMP-activated protein kinase (AMPK) orchestrates the regulation of energy-generating and -consuming pathways, and protects the heart against ischaemic injury and apoptosis. A role for circulating hormones such as adiponectin and leptin in the activation of AMPK has received recent attention. Whether local autocrine and paracrine factors within target organs such as the heart modulate AMPK is unknown. Here we show that macrophage migration inhibitory factor (MIF), an upstream regulator of inflammation, is released in the ischaemic heart, where it stimulates AMPK activation through CD74, promotes glucose uptake and protects the heart during ischaemia-reperfusion injury. Germline deletion of the Mif gene impairs ischaemic AMPK signalling in the mouse heart. Human fibroblasts with a low-activity MIF promoter polymorphism have diminished MIF release and AMPK activation during hypoxia. Thus, MIF modulates the activation of the cardioprotective AMPK pathway during ischaemia, functionally linking inflammation and metabolism in the heart. We anticipate that genetic variation in MIF expression may impact on the response of the human heart to ischaemia by the AMPK pathway, and that diagnostic MIF genotyping might predict risk in patients with coronary artery disease.     

PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression

Functional impairment of T cells is characteristic of many chronic mouse and human viral infections. The inhibitory receptor programmed death 1 (PD-1; also known as PDCD1), a negative regulator of activated T cells, is markedly upregulated on the surface of exhausted virus-specific CD8 T cells in mice. Blockade of this pathway using antibodies against the PD ligand 1 (PD-L1, also known as CD274) restores CD8 T-cell function and reduces viral load. To investigate the role of PD-1 in a chronic human viral infection, we examined PD-1 expression on human immunodeficiency virus (HIV)-specific CD8 T cells in 71 clade-C-infected people who were naive to anti-HIV treatments, using ten major histocompatibility complex (MHC) class I tetramers specific for frequently targeted epitopes. Here we report that PD-1 is significantly upregulated on these cells, and expression correlates with impaired HIV-specific CD8 T-cell function as well as predictors of disease progression: positively with plasma viral load and inversely with CD4 T-cell count. PD-1 expression on CD4 T cells likewise showed a positive correlation with viral load and an inverse correlation with CD4 T-cell count, and blockade of the pathway augmented HIV-specific CD4 and CD8 T-cell function. These data indicate that the immunoregulatory PD-1/PD-L1 pathway is operative during a persistent viral infection in humans, and define a reversible defect in HIV-specific T-cell function. Moreover, this pathway of reversible T-cell impairment provides a potential target for enhancing the function of exhausted T cells in chronic HIV infection.     

Graphene-based composite materials

Graphene sheets--one-atom-thick two-dimensional layers of sp2-bonded carbon--are predicted to have a range of unusual properties. Their thermal conductivity and mechanical stiffness may rival the remarkable in-plane values for graphite (approximately 3,000 W m(-1) K(-1) and 1,060 GPa, respectively); their fracture strength should be comparable to that of carbon nanotubes for similar types of defects; and recent studies have shown that individual graphene sheets have extraordinary electronic transport properties. One possible route to harnessing these properties for applications would be to incorporate graphene sheets in a composite material. The manufacturing of such composites requires not only that graphene sheets be produced on a sufficient scale but that they also be incorporated, and homogeneously distributed, into various matrices. Graphite, inexpensive and available in large quantity, unfortunately does not readily exfoliate to yield individual graphene sheets. Here we present a general approach for the preparation of graphene-polymer composites via complete exfoliation of graphite and molecular-level dispersion of individual, chemically modified graphene sheets within polymer hosts. A polystyrene-graphene composite formed by this route exhibits a percolation threshold of approximately 0.1 volume per cent for room-temperature electrical conductivity, the lowest reported value for any carbon-based composite except for those involving carbon nanotubes; at only 1 volume per cent, this composite has a conductivity of approximately 0.1 S m(-1), sufficient for many electrical applications. Our bottom-up chemical approach of tuning the graphene sheet properties provides a path to a broad new class of graphene-based materials and their use in a variety of applications.     

A regular period for Saturn's magnetic field that may track its internal rotation

The rotation rate of a planet is one of its fundamental properties. Saturn's rotation, however, is difficult to determine because there is no solid surface from which to time it, and the alternative 'clock'--the magnetic field--is nearly symmetrically aligned with the rotation axis. Radio emissions, thought to provide a proxy measure of the rotation of the magnetic field, have yielded estimates of the rotation period between 10 h 39 min 22 s and 10 h 45 min 45 s (refs 8-10). Because the period determined from radio measurements exhibits large time variations, even on timescales of months, it has been uncertain whether the radio-emission periodicity coincides with the inner rotation rate of the planet. Here we report magnetic field measurements that revealed a time-stationary magnetic signal with a period of 10 h 47 min 6 s +/- 40 s. The signal appears to be stable in period, amplitude and phase over 14 months of observations, pointing to a close connection with the conductive region inside the planet, although its interpretation as the 'true' inner rotation period is still uncertain.     

Restoring function in exhausted CD8 T cells during chronic viral infection

Functional impairment of antigen-specific T cells is a defining characteristic of many chronic infections, but the underlying mechanisms of T-cell dysfunction are not well understood. To address this question, we analysed genes expressed in functionally impaired virus-specific CD8 T cells present in mice chronically infected with lymphocytic choriomeningitis virus (LCMV), and compared these with the gene profile of functional memory CD8 T cells. Here we report that PD-1 (programmed death 1; also known as Pdcd1) was selectively upregulated by the exhausted T cells, and that in vivo administration of antibodies that blocked the interaction of this inhibitory receptor with its ligand, PD-L1 (also known as B7-H1), enhanced T-cell responses. Notably, we found that even in persistently infected mice that were lacking CD4 T-cell help, blockade of the PD-1/PD-L1 inhibitory pathway had a beneficial effect on the 'helpless' CD8 T cells, restoring their ability to undergo proliferation, secrete cytokines, kill infected cells and decrease viral load. Blockade of the CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) inhibitory pathway had no effect on either T-cell function or viral control. These studies identify a specific mechanism of T-cell exhaustion and define a potentially effective immunological strategy for the treatment of chronic viral infections.     

Engineering evolution to study speciation in yeasts

The Saccharomyces 'sensu stricto' yeasts are a group of species that will mate with one another, but interspecific pairings produce sterile hybrids. A retrospective analysis of their genomes revealed that translocations between the chromosomes of these species do not correlate with the group's sequence-based phylogeny (that is, translocations do not drive the process of speciation). However, that analysis was unable to infer what contribution such rearrangements make to reproductive isolation between these organisms. Here, we report experiments that take an interventionist, rather than a retrospective approach to studying speciation, by reconfiguring the Saccharomyces cerevisiae genome so that it is collinear with that of Saccharomyces mikatae. We demonstrate that this imposed genomic collinearity allows the generation of interspecific hybrids that produce a large proportion of spores that are viable, but extensively aneuploid. We obtained similar results in crosses between wild-type S. cerevisiae and the naturally collinear species Saccharomyces paradoxus, but not with non-collinear crosses. This controlled comparison of the effect of chromosomal translocation on species barriers suggests a mechanism for the generation of redundancy in the S. cerevisiae genome.