Heterosis is important for conventional plant breeding and is intensively used to increase the productivity of crop plants. Genetic processes shortly after fertilization might be of particular importance with respect to heterosis, because coordination of the diverse genomes establishes a basis for future performance of the sporophyte. Here we demonstrate a strong crossbreeding advantage of hybrid maize embryos as early as 6 days after fertilization in a modern maize hybrid and provide the first embryo specific analysis of associated gene expression pattern at this early stage of development. We identified differentially expressed genes between hybrid embryos and the parental genotypes by a combined approach of suppression subtractive hybridization and differential screening by microarray hybridizations. Association of heterosis in embryos with genes related to signal transduction and other regulatory processes was implied by the enrichment of these functional classes among the identified gene set. Quantitative RT-PCR analysis validated the expression pattern of 7 of 12 genes analysed and revealed predominantly additive, but also dominant and overdominant expression patterns in hybrid embryos. These patterns indicate that gene regulatory interactions among parental alleles act at this early developmental stage and the genes identified provide entry points for the exploration of gene regulatory networks associated with the specification of the phenomenon heterosis in the plant life cycle.

Cyclosporine A is an immunosuppressive agent that is used clinically in the prevention of transplant rejection and development of graft-versus-host disease. Recently, cyclosporine A has been shown to possess anti-inflammatory properties and is capable of inhibiting lipopolysaccharide-induced NF-KB activation. Ubiquitin-mediated proteasomal proteolysis plays a critical role in signal-induced NF-KB activation since it regulates both IKB degradation and pl05 processing, it is also involved in the production of peptides for the assembly of MHC class I molecules. We report here that cylcosporine A acts as an uncompetitive inhibitor of the chymotrypsin-like activity of the 20S proteasome in vitro and that it suppresses lipopolysaccharide-induced IKB degradation and pl05 processing in vivo demonstrating that inhibition of proteasome proteolysis is the mechanism by which cyclosporine A prevents NF-KB activation. A structurally unrelated immunosuppressant, rapamycin, did not inhibit the 20S proteasome in vitro.

The UK and Europe have seen successive outbreaks of highly pathogenic avian influenza across the 2020/21 and 2021/22 autumn/winter seasons. Understanding both the epidemiology and transmission of these viruses in different species is critical to aid mitigating measures where outbreaks cause extensive mortalities in both land- and waterfowl. Infection of different species can result in mild or asymptomatic outcomes, or acute infections that result in high morbidity and mortality levels. Definition of disease outcome in different species is of great importance to understanding the role different species play in the maintenance and transmission of these pathogens. Further, the infection of species that have conservation value is also important to recognise and characterise to understand the impact on what might be limited wild populations. Highly pathogenic avian influenza virus H5N1 clade 2.3.4.4b has been detected in great skuas (Stercorarius skua) across different colonies on islands off the shore of Scotland, Great Britain during summer 2021. A large number of great skuas were observed as developing severe clinical disease and dying during the epizootic and mortalities were estimated to be high where monitored. Of eight skuas submitted for post-mortem examination, seven were confirmed as being infected with this virus using a range of diagnostic assays. Here we overview the outbreak event that occurred in this species, listed as species of conservation concern in Great Britain and outline the importance of this finding with respect to virus transmission and maintenance.

Purpose: Agents inhibiting the epidermal growth factor receptor (EGFR) have shown clinical benefit in a subset of non^small cell lung cancer patients expressing amplified or mutationally activated EGFR. However, responsive patients can relapse as a result of selection for EGFR gene mutations that confer resistance to ATP competitive EGFR inhibitors, such as erlotinib and gefitinib.We describe here the activity of EXEL-7647 (XL647), a novel spectrum-selective kinase inhibitor with potent activity against the EGF and vascular endothelial growth factor receptor tyrosine kinase families, against both wild-type (WT) and mutant EGFR in vitro and in vivo. Experimental Design: The activity of EGFR inhibitors against WTand mutant EGFRs and their effect on downstream signal transduction was examined in cellular assays and in vivo using A431 and MDA-MB-231 (WT EGFR) and H1975 (L858R andT790M mutant EGFR) xenograft tumors.Results: EXEL-7647 shows potent and long-lived inhibition of the WT EGFR in vivo. In addition, EXEL-7647 inhibits cellular proliferation and EGFR pathway activation in the erlotinib-resistant H1975 cell line that harbors a double mutation (L858R and T790M) in the EGFR gene. In vivo efficacy studies show that EXEL-7647 substantially inhibited the growth of H1975 xenograft tumors and reduced both tumor EGFR signaling and tumor vessel density. Additionally, EXEL-7647, in contrast to erlotinib, substantially inhibited the growth and vascularization of MDA-MB-231 xenografts, a model which is more reliant on signaling through vascular endothelial growth factor receptors. Conclusions: These studies provide a preclinical basis for clinical trials of XL647 in solid tumors and in patients bearing tumors that are resistant to existing EGFR-targeted therapies.

Hybrid vigor or heterosis results from the combination of genetically distant genomes at fertilization, and as well as being of major commercial importance, it is held to contribute significantly to fitness [1]. Activation of the paternal genome marks the transition from maternal to zygotic control of development, but a reported delay of paternal-genome activation in flowering plants [2-4] and animals [5, 6] excludes heterosis from impacting on very early development. We have analyzed the allele-specific expression of 25 genes after fertilization of the egg in maize and show immediate equivalent parental genomic contribution to the zygote. Every gene expressed before the first cell division of the zygotes showed paternal transcripts. Sequence comparisons indicate that these genes are involved in a range of processes and are distributed throughout the genome. Our findings confirm that some plant species have evolved a strategy to activate the paternal genome immediately after fertilization, in contrast to the situation in other plants and in animals. Such an extensive activation of the paternal genome very early in development is consonant with observations of high levels of heterosis in early hybrid maize embryos [7, 8], indicating a significant impact of this sexual strategy on fitness.