Key Points• B cells rapidly downregulate CD1d expression after EBV infection, thus abrogating iNKT cell recognition.• EBV-infected B cells induced to express CD1d elicit iNKT cell functions even in the absence of exogenous antigen.Individuals with X-linked lymphoproliferative disease lack invariant natural killer T (iNKT) cells and are exquisitely susceptible to Epstein-Barr virus (EBV) infection. To determine whether iNKT cells recognize or regulate EBV, resting B cells were infected with EBV in the presence or absence of iNKT cells. The depletion of iNKT cells increased both viral titers and the frequency of EBV-infected B cells. However, EBV-infected B cells rapidly lost expression of the iNKT cell receptor ligand CD1d, abrogating iNKT cell recognition. To determine whether induced CD1d expression could restore iNKT recognition in EBVinfected cells, lymphoblastoid cell lines (LCL) were treated with AM580, a synthetic retinoic acid receptor-a agonist that upregulates CD1d expression via the nuclear protein, lymphoid enhancer-binding factor 1 (LEF-1). AM580 significantly reduced LEF-1 association at the CD1d promoter region, induced CD1d expression on LCL, and restored iNKT recognition of LCL. CD1d-expressing LCL elicited interferon g secretion and cytotoxicity by iNKT cells even in the absence of exogenous antigen, suggesting an endogenous iNKT antigen is expressed during EBV infection. These data indicate that iNKT cells may be important for early, innate control of B cell infection by EBV and that downregulation of CD1d may allow EBV to circumvent iNKT cell-mediated immune recognition. (Blood. 2013;122(15):2600-2608

BASIC AND TRANSLATIONAL AT might be developed as a cell-based therapy for intestinal inflammatory disorders.

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Cancer is associated with immune dysfunction characterized by the presence of proinflammatory and immunosuppressive cells and factors that contribute to tumor growth and progression. Here we show that mammary tumor growth is associated with defects in hematopoiesis, leading to myeloproliferative-like disease (leukemoid reaction), anemia, and disruption of the bone marrow stem/progenitor compartment. The defects we characterized included impaired erythropoiesis, leukocytosis, loss of early progenitor cells in the bone marrow, and splenic extramedullary hematopoiesis. We established an in vitro model to dissect interactions between mammary cancers and the hematopoietic system. Investigations in this model revealed that granulocyte colonystimulating factor (G-CSF) produced by mammary tumors can synergize with FLT3L and granulocyte macrophage CSF (GM-CSF) to expand myeloid progenitors and their progeny in culture. Mammary tumor growth was associated with histone methylation changes within lineage-negative c-Kit-positive hematopoietic cells within the bone marrow of tumor-bearing mice. Similarly, parallel histone methylation patterns occurred in cultured bone marrow cells exposed to mammary tumor-conditioned cell culture media. Notably, changes in histone methylation in these cell populations correlated with dysregulated expression of genes controlling hematopoietic lineage commitment and differentiation, including Hox family genes and members of the Polycomb repressive complex 2 (PRC2) chromatin-remodeling complex. Together, our results show that mammary tumor-secreted factors induce profound perturbations in hematopoiesis and expression of key hematopoietic regulatory genes.

Results showed that using the NIST/JET ceiling jet algorithm gave a closer prediction of the sprinkler response time in a small room than Alpert's correlation. This was expected, since the former includes the effect of a hot upper layer while the latter applies to unconfined ceilings. The experiments available for comparison had been conducted inside an enclosure with a developing hot upper layer. The findings also signified that changing the sprinkler operational parameters can change the predicted sprinkler activation time significantly.

Estimation of causal interactions between brain areas is necessary for elucidating large-scale functional brain networks underlying behavior and cognition. Granger causality analysis of time series data can quantitatively estimate directional information flow between brain regions. Here, we show that such estimates are significantly improved when the temporal sampling rate of functional magnetic resonance imaging (fMRI) is increased 20-fold. Specifically, healthy volunteers performed a simple visuomotor task during blood oxygenation level dependent (BOLD) contrast based whole-head inverse imaging (InI). Granger causality analysis based on raw InI BOLD data sampled at 100-ms resolution detected the expected causal relations, whereas when the data were downsampled to the temporal resolution of 2 s typically used in echo-planar fMRI, the causality could not be detected. An additional control analysis, in which we SINC interpolated additional data points to the downsampled time series at 0.1-s intervals, confirmed that the improvements achieved with the real InI data were not explainable by the increased time-series length alone. We therefore conclude that the high-temporal resolution of InI improves the Granger causality connectivity analysis of the human brain.

Histone deactylase inhibitors (HDACi) are common chemotherapeutic agents that stimulate Epstein-Barr virus (EBV) reactivation; the detailed mechanism remains obscure. In this study, it is demonstrated that PKCd is required for induction of the EBV lytic cycle by HDACi. Inhibition of PKCd abrogates HDACi-mediated transcriptional activation of the Zta promoter and downstream lytic gene expression. Nuclear translocation of PKCd is observed following HDACi stimulation and its overexpression leads to progression of the EBV lytic cycle. Our study suggests that PKCd is a crucial mediator of EBV reactivation and provides a novel insight to study the regulation of the EBV lytic cycle.Epstein-Barr virus (EBV) is a human gammaherpesvirus with both latent and lytic states in its life cycle (Kieff & Rickinson, 2001). EBV reactivation not only produces infectious viral progeny, but also contributes to the development of EBV-related disease (Kieff & Rickinson, 2001). Although the majority of EBV infections in vivo are latent, serological studies suggest that EBV reactivation may occur months or years before the clinical diagnosis of nasopharyngeal carcinoma (NPC), Hodgkin's disease and endemic Burkitt's lymphoma, serving as a risk factor for cancer development (Kieff & Rickinson, 2001). Previous studies have shown that some physiological stimuli and pharmacological agents, including transforming growth factor beta, cross-linking of surface immunoglobulin, phorbol ester, histone deacetylase inhibitors (HDACi) and several genotoxic agents, can induce EBV from latent status into the lytic cycle (Daibata et al., 1994;Davies et al., 1991;Feng & Kenney, 2006; Feng et al., 2002;Schuster et al., 1991).The protein kinase C (PKC) family has been known for a long time to be necessary for EBV reactivation following stimulation with 12-O-tetradecanoyl phorbol 13-acetate (TPA) (Davies et al., 1991) or anti-immunoglobulin treatment (Daibata et al., 1994). The PKC family comprises 11 isozymes, which are classified into three subfamilies according to their structure and regulatory domains activated by calcium or diacylglycerol (DAG) (Newton, 1997). Conventional PKCs (PKCa, bI, bII and c) require calcium and DAG activators, and novel PKCs (PKCd, e, h and g) respond only to DAG and not to calcium (Newton, 1997). However, atypical PKC isoforms (PKCf, i/l and m) are DAG-insensitive (Newton, 1997). Until now, it has not been clear which PKC members are involved in EBV reactivation. The limited information available suggests that PKCs may play an important role during different stages of various virus infections (Constantinescu et al., 1991;Sieczkarski et al., 2003). For example, PKCf or PKCd is required for early infection or TPA-triggered lytic-cycle activation of Kaposi's sarcoma-associated herpesvirus (KSHV) (Deutsch et al., 2004;Naranatt et al., 2003).HDACi, including trichostatin A (TSA), sodium butyrate (SB) and valproic acid, are common agents used to induce the EBV lytic cycle in several EBV-harbouring epithelial and B cells (Chang & Liu, 2...

By tuning the chemical modalities on gold nanoparticle surface using hexapeptide ligands the responses of immune cells (dendritic cells) to nanoparticles can be remarkably manipulated from minimum reaction (in the presence of negatively charged peptide ligands) to activation (in the presence of peptide ligands with aromatic rings containing amino acids).