T-Bet and Eomes Regulate the Balance between the Effector/Central Memory T Cells versus Memory Stem Like T Cells

Memory T cells are composed of effector, central, and memory stem cells. Previous studies have implicated that both T-bet and Eomes are involved in the generation of effector and central memory CD8 T cells. The exact role of these transcription factors in shaping the memory T cell pool is not well understood, particularly with memory stem T cells. Here, we demonstrate that both T-bet or Eomes are required for elimination of established tumors by adoptively transferred CD8 T cells. We also examined the role of T-bet and Eomes in the generation of tumor-specific memory T cell subsets upon adoptive transfer. We showed that combined T-bet and Eomes deficiency resulted in a severe reduction in the number of effector/central memory T cells but an increase in the percentage of CD62LhighCD44low Sca-1+ T cells which were similar to the phenotype of memory stem T cells. Despite preserving large numbers of phenotypic memory stem T cells, the lack of both of T-bet and Eomes resulted in a profound defect in antitumor memory responses, suggesting T-bet and Eomes are crucial for the antitumor function of these memory T cells. Our study establishes that T-bet and Eomes cooperate to promote the phenotype of effector/central memory CD8 T cell versus that of memory stem like T cells. © 2013 Li et al

The European Union in the World — A Community of Values

These are momentous times in Europe. The Euro has been successfully introduced, the enlargement negotiations are approaching their climax, and the European Convention (“Convention”) is moving towards the drafting of a constitution for a new, continent-wide political entity. At the same time, unrest is manifest, particularly in two areas. On the one hand, many of our citizens, and not just the political elites, are dissatisfied with Europe\u27s performance on the world stage and are concerned about the maintenance of peace and security within the Union. In these areas they would like to see a strengthened, more effective entity-- “more Europe.” On the other hand, their disenchantment with the long reach of European Union (“EU” or “Union”) regulation in the first pillar area of economic policy is growing. The feeling of loss of local control over their destiny and a vague feeling of potential loss of identity within an ever more centralized polity is palpable. Here, they want “less Europe.” In the outside world, change is also the order of the day. The ice-sheet of bipolarity, which overlaid and hid the complexity of international relations during the Cold War, is breaking up at an ever-increasing speed and revealing a world in which two paradigms are competing to become the underlying ordering principles for the new century. The traditional paradigm of interacting Nation States, each pursuing its own separate interests, with alliances allowing the small to compete with the large, is alive and well, and its proponents like Machiavelli or Churchill continue to be in vogue in the literature of international relations and the rhetoric of world leaders. At the same time, there is a school of thought which points to the growing economic and ecological interdependence of our societies and the necessity for new forms of global governance to complement national action. It is also becoming abundantly clear that the concept of a “Nation State” is often a fiction, positing as it does an identity between the citizens of a State and the members of a culturally homogenous society. For both reasons, the concept of the Nation State as the principal actor on the world stage, is called into question. The experience of the Union with the sharing of State sovereignty is clearly related to the second paradigm and also to the EU\u27s firm support for the development of the United Nations (“U.N.”) as well as other elements of multilateral governance. It would hardly be wise to suggest that any foreign policy, and certainly not that of the EU, should be based only on this paradigm. Given the recurrent threats to security, which seem to be part of the human condition expressed by some as the “inevitability of war”--the defense of territorial integrity; action against threats of aggression; and resistance to crimes against humanity such as genocide--the ability to conduct a security policy based much more on the old paradigm of interacting interests will continue to be required. That the EU needs to develop such a capability will be taken here as a given. Such a crisis-management capability will be essential to the Union, but will be distinguished here from the more long-term elements of foreign policy, which can be thought of as being designed to reduce the need for crisis management in the context of a security policy to a minimum. The crisis-management area of policy will not be treated further here. The thesis of this Essay is that the same set of political concepts can serve as a guide to the future internal development of the EU and as the basis of such a long-term foreign policy. Furthermore, it suggests that neither should be seen in terms of the balancing of interests but rather, as the expression of a small list of fundamental values. The list is as follows: (1) the rule of law as the basis for relations between members of society; (2) the interaction between the democratic process and entrenched human rights in political decision-making; (3) the operation of competition within a market economy as the source of increasing prosperity; (4) the anchoring of the principle of solidarity among all members of society alongside that of the liberty of the individual; (5) the adoption of the principle of sustainability of all economic development; and (6) the preservation of separate identities and the maintenance of cultural diversity within society. These values can be seen as the answer to the question posed both, by citizens of the Union and by our fellow citizens of the world: “What does the EU stand for?” In exploring these values we should, however, remember that in the real world there will be occasions on which Realpolitik will intrude and the interest-based paradigm will prevail

Synergistic toughening of composite fibres by self-alignment of reduced graphene oxide and carbon nanotubes

The extraordinary properties of graphene and carbon nanotubes motivate the development of methods for their use in producing continuous, strong, tough fibres. Previous work has shown that the toughness of the carbon nanotube-reinforced polymer fibres exceeds that of previously known materials. Here we show that further increased toughness results from combining carbon nanotubes and reduced graphene oxide flakes in solution-spun polymer fibres. The gravimetric toughness approaches 1,000 J g−1, far exceeding spider dragline silk (165 J g−1) and Kevlar (78 J g−1). This toughness enhancement is consistent with the observed formation of an interconnected network of partially aligned reduced graphene oxide flakes and carbon nanotubes during solution spinning, which act to deflect cracks and allow energy-consuming polymer deformation. Toughness is sensitive to the volume ratio of the reduced graphene oxide flakes to the carbon nanotubes in the spinning solution and the degree of graphene oxidation. The hybrid fibres were sewable and weavable, and could be shaped into high-modulus helical springs

Measurement of the single-spin asymmetry A y 0 in quasi-elastic 3He↑(e,e′n) scattering at 0.4 < Q 2 < 1.0 GeV/c 2

No abstract available

The histone deacetylase inhibitor Trichostatin A modulates CD4+ T cell responses

BACKGROUND: Histone deacetylase inhibitors (HDACIs) induce hyperacetylation of core histones modulating chromatin structure and affecting gene expression. These compounds are also able to induce growth arrest, cell differentiation, and apoptotic cell death of tumor cells in vitro as well as in vivo. Even though several genes modulated by HDAC inhibition have been identified, those genes clearly responsible for the biological effects of these drugs have remained elusive. We investigated the pharmacological effect of the HDACI and potential anti-cancer agent Trichostatin A (TSA) on primary T cells. METHODS: To ascertain the effect of TSA on resting and activated T cells we used a model system where an enriched cell population consisting of primary T-cells was stimulated in vitro with immobilized anti-CD3/anti-CD28 antibodies whilst exposed to pharmacological concentrations of Trichostatin A. RESULTS: We found that this drug causes a rapid decline in cytokine expression, accumulation of cells in the G(1 )phase of the cell cycle, and induces apoptotic cell death. The mitochondrial respiratory chain (MRC) plays a critical role in the apoptotic response to TSA, as dissipation of mitochondrial membrane potential and reactive oxygen species (ROS) scavengers block TSA-induced T-cell death. Treatment of T cells with TSA results in the altered expression of a subset of genes involved in T cell responses, as assessed by microarray gene expression profiling. We also observed up- as well as down-regulation of various costimulatory/adhesion molecules, such as CD28 and CD154, important for T-cell function. CONCLUSIONS: Taken together, our findings indicate that HDAC inhibitors have an immunomodulatory potential that may contribute to the potency and specificity of these antineoplastic compounds and might be useful in the treatment of autoimmune disorders

Histone deacetylase (HDAC) inhibitors in recent clinical trials for cancer therapy

Heritable changes in gene expression that are not based upon alterations in the DNA sequence are defined as epigenetics. The most common mechanisms of epigenetic regulation are the methylation of CpG islands within the DNA and the modification of amino acids in the N-terminal histone tails. In the last years, it became evident that the onset of cancer and its progression may not occur only due to genetic mutations but also because of changes in the patterns of epigenetic modifications. In contrast to genetic mutations, which are almost impossible to reverse, epigenetic changes are potentially reversible. This implies that they are amenable to pharmacological interventions. Therefore, a lot of work in recent years has focussed on the development of small molecule enzyme inhibitors like DNA-methyltransferase inhibitors or inhibitors of histone-modifying enzymes. These may reverse misregulated epigenetic states and be implemented in the treatment of cancer or other diseases, e.g., neurological disorders. Today, several epigenetic drugs are already approved by the FDA and the EMEA for cancer treatment and around ten histone deacetylase (HDAC) inhibitors are in clinical development. This review will give an update on recent clinical trials of the HDAC inhibitors used systemically that were reported in 2009 and 2010 and will present an overview of different biomarkers to monitor the biological effects

Energy loss due to defect formation from \u3csup\u3e206\u3c/sup\u3ePb recoils in SuperCDMS germanium detectors

The Super Cryogenic Dark Matter Search experiment (SuperCDMS) at the Soudan Underground Laboratory studied energy loss associated with Frenkel defect formation in germanium crystals at mK temperatures using in situ 210Pb sources. We examine the spectrum of 206Pb nuclear recoils near its expected 103 keV endpoint energy and determine an energy loss of (6.08±0.18) %, which we attribute to defect formation. From this result and using TRIM simulations, we extract the first experimentally determined average displacement threshold energy of (19.7+0.6−0.5) eV for germanium. This has implications for the analysis thresholds of future germanium-based dark matter searches