Decreased Responsiveness of Mature Dendritic Cells from Cord Blood to Chemotaxis Induced by CXCR4 Ligand CXCL12, and CCR7 Ligand CCL19 May Explain Lowered GVHD Associated with Cord Blood Tranplantation.

Abstract Cord blood has been successfully used as a transplantable source of hemopoietic stem cells with a relatively low incidence of graft-versus-host disease (GVHD). Mature dendritic cells (DC), as the most efficient antigen presenting cells, play a critical role in the pathogenesis of GVHD and their function is intimately linked to their capacity to migrate. Chemokines and their G-protein linked receptors are of particular importance in DC migration. CCR7 and CXCR4 are two chemokine receptors expressed on mature DC. Binding of CCR7 ligand, MIP-3β/CCL19 and CXCR4 ligand, SDF-1/CXCL12 induce chemotaxis of mature DC and are pivotal for DC to initiate their functions in vivo. We hypothesized that the relatively lowered level of GVHD elicited by cord blood, compared to adult cells, might be due, at least in part, to a reduced capability of cord blood DC to migrate to lymphoid organs to initiate immune reactions and to organs such as liver and skin where GVHD pathogenesis usually occurs. To begin testing this hypothesis, we randomly picked 16 cord blood donors and 14 adult blood donors and did paired comparison study on chemotactic responses of cord blood and adult blood DC to CXCL12 and CCL19. Monocytes were isolated from both cord blood and adult blood and cultured with GM-CSF and IL-4 for 5 days to generate immature DC. LPS was added into cell culture for an additional 1 day to induce the maturation of these DC. Mature DC were harvested on day 6. We found that cord blood DC expressed significantly reduced surface levels of CCR7 compared with that of adult blood DC (p = .00067) and migrated at significantly lower efficiency towards the CCR7 ligand, CCL19 than did adult blood DC (p=0.029). Cord blood DC expressed significantly higher surface expression of CXCR4 than adult blood DC (p = .0018), but migrated at significantly lower efficiency towards CXCR4 ligand, CXCL12 than adult blood DC (p=0.00012). The lowered responsiveness of mature cord blood DC to chemotaxis by CXCL12 may reflect the enhanced truncation of CXCR4 we found on these cells. Also, cord blood DC migrated less well than adult blood DC toward the combination of CXCL12 and CCL19 than adult blood DC (p = .0014). These results suggest that low incidence and pathogenesis of GVHD observed in cord blood might be due, at least in part, to reduced capability of cord blood mature DC to migrate to critical organs where immune reaction and inflammation occur, effects reflecting lowered expression of CCR7 and enhanced truncation of CXCR4 on mature cord blood DC.</jats:p

Influence of ERK activation on decreased chemotaxis of mature human cord blood monocyte–derived dendritic cells to CCL19 and CXCL12

Dendritic cells (DCs) are important regulators in graft-versus-host disease (GVHD). To gain insight into cord blood (CB) DC immunology, we compared chemotactic responses of mature monocyte-derived DCs and maturation agent lipopolysaccharide (LPS)–induced signaling between CB and adult blood (AB). Mature CB DCs expressed reduced CCR7, but increased CXCR4. This was associated with reduced migratory efficiency toward both CCR7 ligand CCL19 and CXCR4 ligand CXCL12. LPS induced higher extracellular signal-regulated kinase (ERK) phosphorylation in CB than in AB DCs. Specific inhibition of ERK during CB DC maturation enhanced LPS-induced up-regulation of CCR7 and CXCR4 on CB DCs and their chemotaxis toward CCL19 and CXCL12, to a level similar to that of mature AB DCs. Overall, monocyte-derived CB DCs responded to LPS with stronger and sustained ERK activation, which negatively correlated with LPS-induced up-regulation of CCR7 and CXCR4 on CB DCs and their migratory responses. These findings may have potential relevance to better understanding DC function in CB transplantation

Breaking ground in cross-cultural research on the fear of being laughed at (gelotophobia): A multi-national study involving 73 countries

The current study examines whether the fear of being laughed at (gelotophobia) can be assessed reliably and validly by means of a self-report instrument in different countries of the world. All items of the GELOPH (Ruch and Titze, GELOPH46, University of Düsseldorf, 1998; Ruch and Proyer, Swiss Journal of Psychology 67:19–27, 2008b) were translated to the local language of the collaborator (42 languages in total). In total, 22,610 participants in 93 samples from 73 countries completed the GELOPH. Across all samples the reliability of the 15-item questionnaire was high (mean alpha of .85) and in all samples the scales appeared to be unidimensional. The endorsement rates for the items ranged from 1.31% through 80.00% to a single item. Variations in the mean scores of the items were more strongly related to the culture in a country and not to the language in which the data were collected. This was also supported by a multidimensional scaling analysis with standardized mean scores of the items from the GELOPH15. This analysis identified two dimensions that further helped explaining the data (i.e., insecure vs. intense avoidant-restrictive and low vs. high suspicious tendencies towards the laughter of others). Furthermore, multiple samples derived from one country tended to be (with a few exceptions) highly similar. The study shows that gelotophobia can be assessed reliably by means of a self-report instrument in cross-cultural research. This study enables further studies of the fear of being laughed at with regard to differences in the prevalence and putative causes of gelotophobia in comparisons to different cultures

Conditional QTL Analysis and Fine Mapping for Thousand-Kernel Weight in Common Wheat

To elucidate the genetic basis of thousand-kernel weight (TKW) related to fundamental traits such as kernel length (KL), kernel width (KW), and kernel diameter ratio (KDR) at the individual quantitative trait loci (QTL) level, both unconditional QTL analysis and conditional QTL analysis for TKW were analyzed using a recombinant inbred line (RIL) population, along with a simplified physical map. A total of 37 unconditional QTLs and 34 conditional QTLs were identified. Six QTLs exhibited independent effects from individual traits (KL, KW, or KDR), while 18 QTLs showed common influences from two or three of these traits simultaneously. Additionally, 26 pairs of epistatically interacting QTLs involving 16 loci were detected. Subsequently, fine mapping of the stable and major-effect QTL QTkw1B was carried out using the derived near-isogenic lines (NILs), ultimately locating it within the interval of 698.15&ndash;700.19 Mb on chromosome 1B of the KN9204 genome. The conditional QTL analysis and genetic effect analysis based on NILs both indicated that the increase in TKW was primarily contributed by kernel length. The QTL identified in the present study through the combination of conditional and unconditional QTL mapping could increase the understanding of the genetic interrelationships between TKW and kernel size traits at the individual QTL level and provide a theoretical basis for subsequent candidate gene mining