The role of the Runx transcription factors in thymocyte differentiation and in homeostasis of naive T cells

Members of the Runx family of transcriptional regulators are required for the appropriate expression of CD4 and CD8 at discrete stages of T cell development. The roles of these factors in other aspects of T cell development are unknown. We used a strategy to conditionally inactivate the genes encoding Runx1 or Runx3 at different stages of thymocyte development, demonstrating that Runx1 regulates the transitions of developing thymocytes from the CD4−CD8− double-negative stage to the CD4+CD8+ double-positive (DP) stage and from the DP stage to the mature single-positive stage. Runx1 and Runx3 deficiencies caused marked reductions in mature thymocytes and T cells of the CD4+ helper and CD8+ cytotoxic T cell lineages, respectively. Runx1-deficient CD4+ T cells had markedly reduced expression of the interleukin 7 receptor and exhibited shorter survival. In addition, inactivation of both Runx1 and Runx3 at the DP stages resulted in a severe block in development of CD8+ mature thymocytes. These results indicate that Runx proteins have important roles at multiple stages of T cell development and in the homeostasis of mature T cells

Discrete approaches to quantum gravity in four dimensions

The construction of a consistent theory of quantum gravity is a problem in theoretical physics that has so far defied all attempts at resolution. One ansatz to try to obtain a non-trivial quantum theory proceeds via a discretization of space-time and the Einstein action. I review here three major areas of research: gauge-theoretic approaches, both in a path-integral and a Hamiltonian formulation, quantum Regge calculus, and the method of dynamical triangulations, confining attention to work that is strictly four-dimensional, strictly discrete, and strictly quantum in nature.Comment: 33 pages, invited contribution to Living Reviews in Relativity; the author welcomes any comments and suggestion

Bhlhe40 controls cytokine production by T cells and is essential for pathogenicity in autoimmune neuroinflammation

T(H)1 and T(H)17 cells mediate neuroinflammation in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Pathogenic T(H) cells in EAE must produce the pro-inflammatory cytokine granulocyte-macrophage colony stimulating factor (GM-CSF). T(H) cell pathogenicity in EAE is also regulated by cell-intrinsic production of the immunosuppressive cytokine interleukin 10 (IL-10). Here, we demonstrate that mice deficient for the basic helix-loop-helix (bHLH) transcription factor Bhlhe40 (Bhlhe40(−/−)) are resistant to the induction of EAE. Bhlhe40 is required in vivo in a T cell-intrinsic manner, where it positively regulates the production of GM-CSF and negatively regulates the production of IL-10. In vitro, GM-CSF secretion is selectively abrogated in polarized Bhlhe40(−/−) T(H)1 and T(H)17 cells, and these cells show increased production of IL-10. Blockade of IL-10 receptor in Bhlhe40(−/−) mice renders them susceptible to EAE. These findings identify Bhlhe40 as a critical regulator of autoreactive T cell pathogenicity

HPV16 and 18 genome amplification show different E4-dependence, with 16E4 enhancing E1 nuclear accumulation and replicative efficiency via its cell cycle arrest and kinase activation functions

To clarify E1^E4's role during high-risk HPV infection, the E4 proteins of HPV16 and 18 were compared side by side using an isogenic keratinocyte differentiation model. While no effect on cell proliferation or viral genome copy number was observed during the early phase of either virus life cycle, time-course experiments showed that viral genome amplification and L1 expression were differently affected upon differentiation, with HPV16 showing a much clearer E4 dependency. Although E4 loss never completely abolished genome amplification, its more obvious contribution in HPV16 focused our efforts on 16E4. As previously suggested, in the context of the virus life cycle, 16E4s G2-arrest capability was found to contribute to both genome amplification success and L1 accumulation. Loss of 16E4 also lead to a reduced maintenance of ERK, JNK and p38MAPK activity throughout the genome amplifying cell layers, with 16E4 (but not 18E4) co-localizing precisely with activated cytoplasmic JNK in both wild type raft tissue, and HPV16-induced patient biopsy tissue. When 16E1 was co-expressed with E4, as occurs during genome amplification $\textit{in vivo}$, the E1 replication helicase accumulated preferentially in the nucleus, and in transient replication assays, E4 stimulated viral genome amplification. Interestingly, a 16E1 mutant deficient in its regulatory phosphorylation sites no longer accumulated in the nucleus following E4 co-expression. E4-mediated stabilisation of 16E2 was also apparent, with E2 levels declining in organotypic raft culture when 16E4 was absent. These results suggest that 16E4-mediated enhancement of genome amplification involves its cell cycle inhibition and cellular kinase activation functions, with E4 modifying the activity and function of viral replication proteins including E1. These activities of 16E4, and the different kinase patterns seen here with HPV18, 31 and 45, may reflect natural differences in the biology and tropisms of these viruses, as well as differences in E4 function.The work was supported by the UK Medical Research Council (grant ref. MC_PC_13050 / Molecular biology of human papilloma virus infection to JD, http://gtr.rcuk.ac.uk/ project/A691 306C-DAA9- 4078-B5D E- 2096CF3C8A18)

Requirement of Interaction between Mast Cells and Skin Dendritic Cells to Establish Contact Hypersensitivity

The role of mast cells (MCs) in contact hypersensitivity (CHS) remains controversial. This is due in part to the use of the MC-deficient Kit W/Wv mouse model, since Kit W/Wv mice congenitally lack other types of cells as a result of a point mutation in c-kit. A recent study indicated that the intronic enhancer (IE) for Il4 gene transcription is essential for MCs but not in other cell types. The aim of this study is to re-evaluate the roles of MCs in CHS using mice in which MCs can be conditionally and specifically depleted. Transgenic Mas-TRECK mice in which MCs are depleted conditionally were newly generated using cell-type specific gene regulation by IE. Using this mouse, CHS and FITC-induced cutaneous DC migration were analyzed. Chemotaxis assay and cytoplasmic Ca2+ imaging were performed by co-culture of bone marrow-derived MCs (BMMCs) and bone marrow-derived dendritic cells (BMDCs). In Mas-TRECK mice, CHS was attenuated when MCs were depleted during the sensitization phase. In addition, both maturation and migration of skin DCs were abrogated by MC depletion. Consistently, BMMCs enhanced maturation and chemotaxis of BMDC in ICAM-1 and TNF-α dependent manners Furthermore, stimulated BMDCs increased intracellular Ca2+ of MC upon direct interaction and up-regulated membrane-bound TNF-α on BMMCs. These results suggest that MCs enhance DC functions by interacting with DCs in the skin to establish the sensitization phase of CHS

Cultural trauma, counter-narratives, and dialogical intellectuals: the works of Murakami Haruki and Mori Tatsuya in the context of the Aum affair

In this article, we offer a new conceptualization of intellectuals as carriers of cultural trauma through a case study of the Aum Affair, a series of crimes and terrorist attacks committed by the Japanese new religious movement Aum Shinrikyō. In understanding the performative roles intellectuals play in trauma construction, we offer a new dichotomy between “authoritative intellectuals,” who draw on their privileged parcours and status to impose a distinct trauma narrative, and “dialogical intellectuals,” who engage with local actors dialogically to produce polyphonic and open-ended trauma narratives. We identify three dimensions of dialogical intellectual action: firstly, the intellectuals may be involved in dialogue with local participants; secondly, the intellectual products themselves may be dialogical in content; and thirdly, there might be a concerted effort on the part of the intellectuals to record and to disseminate dialogue between local participants. In the context of the Aum Affair, we analyze the works of Murakami Haruki and Mori Tatsuya as dialogical intellectuals while they sought, with the help of local actors’ experiences, to challenge and to alter the orthodox trauma narrative of Aum Shinrikyō as exclusively a social evil external to Japanese society and an enemy to be excluded from it. Towards the end of the article, we discuss the broader significance of this case study and suggest that in light of recent societal and technological developments, the role and scope of dialogical intellectuals as carriers of trauma are changing and possibly expanding

Pion photoproduction on the nucleon in the quark model

We present a detailed quark-model study of pion photoproduction within the effective Lagrangian approach. Cross sections and single-polarization observables are investigated for the four charge channels, $\gamma p\to \pi^+ n$, $\gamma n\to \pi^- p$, $\gamma p\to \pi^0 p$, and $\gamma n\to \pi^0 n$. Leaving the $\pi N\Delta$ coupling strength to be a free parameter, we obtain a reasonably consistent description of these four channels from threshold to the first resonance region. Within this effective Lagrangian approach, strongly constrainted by the quark model, we consider the issue of double-counting which may occur if additional {\it t}-channel contributions are included.Comment: Revtex, 35 pages, 16 eps figures; version to appear on PR

Lineage Diversion of T Cell Receptor Transgenic Thymocytes Revealed by Lineage Fate Mapping

Background: The binding of the T cell receptor (TCR) to major histocompatibility complex (MHC) molecules in the thymus determines fates of $TCR\alpha\beta$ lymphocytes that subsequently home to secondary lymphoid tissue. TCR transgenic models have been used to study thymic selection and lineage commitment. Most TCR transgenic mice express the rearranged $TCR\alpha\beta$ prematurely at the double negative stage and abnormal TCRαβ populations of T cells that are not easily detected in non-transgenic mice have been found in secondary lymphoid tissue of TCR transgenic mice. Methodology and Principal Findings: To determine developmental pathways of TCR-transgenic thymocytes, we used Cre-LoxP-mediated fate mapping and show here that premature expression of a transgenic $TCR\alpha\beta$ diverts some developing thymocytes to a developmental pathway which resembles that of gamma delta cells. We found that most peripheral T cells with the HY-TCR in male mice have bypassed the RORγt-positive $CD4^{+}8^{+}$ (double positive, DP) stage to accumulate either as $CD4^{-}8^{-}$ (double negative, DN) or as $CD8\alpha^{+}$ T cells in lymph nodes or gut epithelium. Likewise, DN $TCR\alpha\beta$ cells in lymphoid tissue of female mice were not derived from DP thymocytes. Conclusion: The results further support the hypothesis that the premature expression of the $TCR\alpha\beta$ can divert DN thymocytes into gamma delta lineage cells

P-wave excited baryons from pion- and photo-induced hyperon production

We report evidence for $N(1710)P_{11}$, $N(1875)P_{11}$, $N(1900)P_{13}$, $\Delta(1600)P_{33}$, $\Delta(1910)P_{31}$, and $\Delta(1920)P_{33}$, and find indications that $N(1900)P_{13}$ might have a companion state at 1970\,MeV. The controversial $\Delta(1750)P_{31}$ is not seen. The evidence is derived from a study of data on pion- and photo-induced hyperon production, but other data are included as well. Most of the resonances reported here were found in the Karlsruhe-Helsinki (KH84) and the Carnegie-Mellon (CM) analyses but were challenged recently by the Data Analysis Center at GWU. Our analysis is constrained by the energy independent $\pi N$ scattering amplitudes from either KH84 or GWU. The two $\pi N$ amplitudes from KH84 or GWU, respectively, lead to slightly different $\pi N$ branching ratios of contributing resonances but the debated resonances are required in both series of fits.Comment: 22 pages, 28 figures. Some additional sets of data are adde