ROCK1/2 signaling contributes to corticosteroid-refractory acute graft-versus-host disease

Patients with corticosteroid-refractory acute graft-versus-host disease (aGVHD) have a low one-year survival rate. Identification and validation of novel targetable kinases in patients who experience corticosteroid-refractory-aGVHD may help improve outcomes. Kinase-specific proteomics of leukocytes from patients with corticosteroid-refractory-GVHD identified rho kinase type 1 (ROCK1) as the most significantly upregulated kinase. ROCK1/2 inhibition improved survival and histological GVHD severity in mice and was synergistic with JAK1/2 inhibition, without compromising graft-versus-leukemia-effects. ROCK1/2-inhibition in macrophages or dendritic cells prior to transfer reduced GVHD severity. Mechanistically, ROCK1/2 inhibition or ROCK1 knockdown interfered with CD80, CD86, MHC-II expression and IL-6, IL-1β, iNOS and TNF production in myeloid cells. This was accompanied by impaired T cell activation by dendritic cells and inhibition of cytoskeletal rearrangements, thereby reducing macrophage and DC migration. NF-κB signaling was reduced in myeloid cells following ROCK1/2 inhibition. In conclusion, ROCK1/2 inhibition interferes with immune activation at multiple levels and reduces acute GVHD while maintaining GVL-effects, including in corticosteroid-refractory settings

Unlocking the Genetic Diversity of Maize Landraces with Doubled Haploids Opens New Avenues for Breeding

<div><p>Landraces are valuable genetic resources for broadening the genetic base of elite germplasm in maize. Extensive exploitation of landraces has been hampered by their genetic heterogeneity and heavy genetic load. These limitations may be overcome by the <i>in-vivo</i> doubled haploid (DH) technique. A set of 132 DH lines derived from three European landraces and 106 elite flint (EF) lines were genotyped for 56,110 single nucleotide polymorphism (SNP) markers and evaluated in field trials at five locations in Germany in 2010 for several agronomic traits. In addition, the landraces were compared with synthetic populations produced by intermating DH lines derived from the respective landrace. Our objectives were to (1) evaluate the phenotypic and molecular diversity captured within DH lines derived from European landraces, (2) assess the breeding potential (usefulness) of DH lines derived from landraces to broaden the genetic base of the EF germplasm, and (3) compare the performance of each landrace with the synthetic population produced from the respective DH lines. Large genotypic variances among DH lines derived from landraces allowed the identification of DH lines with grain yields comparable to those of EF lines. Selected DH lines may thus be introgressed into elite germplasm without impairing its yield level. Large genetic distances of the DH lines to the EF lines demonstrated the potential of DH lines derived from landraces to broaden the genetic base of the EF germplasm. The comparison of landraces with their respective synthetic population showed no yield improvement and no reduction of phenotypic diversity. Owing to the low population structure and rapid decrease of linkage disequilibrium within populations of DH lines derived from landraces, these would be an ideal tool for association mapping. Altogether, the DH technology opens new opportunities for characterizing and utilizing the genetic diversity present in gene bank accessions of maize.</p> </div

Mean performance for agronomic and morphological traits of the landraces <i>Bugard</i>, <i>Gelber Badischer</i> and <i>Schindelmeiser</i>, as well as of the corresponding synthetic populations produced by intermating the respective doubled haploid lines.

†<p>Different letters indicate significant differences among populations for the respective trait.</p>‡<p>1 = absent, 9 = pronounced.</p>§<p>Multiply the reported mean by this value to obtain the actual numbers.</p

Phenotypic distances among elite flint lines and doubled haploid lines derived from landraces.

<p>Pair-wise Euclidean distances among elite flint (EF) lines and doubled haploid (DH) lines derived from the landraces <i>Bugard</i> (DH-BU), <i>Gelber Badischer</i> (DH-GB), and <i>Schindelmeiser</i> (DH-SC) were calculated from 16 morphological and agronomic traits standardized to mean zero and unit variance.</p

Mean, genotypic variance (<i>σ²_g</i>), genotype×environment interaction variance (<i>σ²_ge</i>), heritability (<i>h²</i>), predicted gain from selection (<i>ΔG</i>) and usefulness (<i>U</i>) at selection intensity <i>α</i> for agronomic and morphological traits of doubled haploid (DH) lines derived from the landraces <i>Bugard</i> (DH-BU, n = 36), <i>Gelber Badischer</i> (DH-GB, n = 31) and <i>Schindelmeiser</i> (DH-SC, n = 65), as well as of elite flint lines (EF, n = 106).

*, **<p>Significant at the 0.05, 0.01 probability level, respectively.</p>†<p>Different letters indicate significant differences among the four populations for the respective trait.</p>‡<p>1 = absent, 9 = pronounced.</p>§<p>Multiply the reported mean by this this value and the variance components by the square of this this value to obtain the actual numbers.</p

Mean, genotypic variance (<i>σ²_g</i>), genotype×environment interaction variance (<i>σ²_ge</i>), heritability (<i>h²</i>), predicted gain from selection (<i>ΔG</i>) and usefulness (<i>U</i>) at selection intensity α for grain yield and yield components of doubled haploid (DH) lines derived from the landraces <i>Bugard</i> (DH-BU, n = 36), <i>Gelber Badischer</i> (DH-GB, n = 31) and <i>Schindelmeiser</i> (DH-SC, n = 65), as well as of elite flint lines (EF, n = 106).

*, **<p>Significant at the 0.05, 0.01 probability level, respectively.</p>†<p>Different letters indicate significant differences among the four populations for the respective trait.</p>‡<p>at 420 GDD after flowering.</p