Sweet cherry (Prunus avium) is an economically significant fruit species in the genus Prunus. However, in contrast to other important fruit trees in this genus, only one draft genome assembly is available for sweet cherry, which was assembled using only Illumina short-read sequences. The incompleteness and low quality of the current sweet cherry draft genome limit its use in genetic and genomic studies. A high-quality chromosome-scale sweet cherry reference genome assembly is therefore needed. A total of 65.05 Gb of Oxford Nanopore long reads and 46.24 Gb of Illumina short reads were generated, representing~190x and 136x coverage, respectively, of the sweet cherry genome. The final de novo assembly resulted in a phased haplotype assembly of 344.29 Mb with a contig N50 of 3.25 Mb. Hi-C scaffolding of the genome resulted in eight pseudochromosomes containing 99.59% of the bases in the assembled genome. Genome annotation revealed that more than half of the genome (59.40%) was composed of repetitive sequences, and 40,338 protein-coding genes were predicted, 75.40% of which were functionally annotated. With the chromosomescale assembly, we revealed that gene duplication events contributed to the expansion of gene families for salicylic acid/jasmonic acid carboxyl methyltransferase and ankyrin repeat-containing proteins in the genome of sweet cherry. Four auxin-responsive genes (two GH3s and two SAURs) were induced in the late stage of fruit development, indicating that auxin is crucial for the sweet cherry ripening process. In addition, 772 resistance genes were identified and functionally predicted in the sweet cherry genome. The high-quality genome assembly of sweet cherry obtained in this study will provide valuable genomic resources for sweet cherry improvement and molecular breeding.

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The mutation occurs in approximately 8% of human colorectal cancers and is associated with therapeutic resistance that is due, in part, to reactivation of MEK/ERK signaling cascade. Recently, pathway analysis identified cyclin-dependent kinase 1 (CDK1) upregulation in a subset of human colorectal cancers. Therefore, it was determined whether CDK1 antagonism enhances the efficacy of MEK inhibition in colorectal cancer cells. colorectal cancer cell lines expressing CDK1 were sensitized to apoptosis upon siRNA knockdown or small-molecule inhibition with RO-3306 (CDK1 inhibitor) or dinaciclib (CDK1, 2, 5, 9 inhibitors). Combination of RO-3306 or dinaciclib with cobimetinib (MEK inhibitor) cooperatively enhanced apoptosis and reduced clonogenic survival versus monotherapy. Cells isogenic or ectopic for displayed resistance to CDK1 inhibitors, as did cells with ectopic expression of constitutively active CDK1 inhibitors induced a -dependent apoptosis shown by caspase-8 restoration in deficient NB7 cells that enhanced dinaciclib-induced CASP3 cleavage. CDK inhibitors suppressed pro-CASP8 phosphorylation at S387, as shown by drug withdrawal, which restored p-S387 and increased mitosis. In a colorectal cancer xenograft model, dinaciclib plus cobimetinib produced significantly greater tumor growth inhibition in association with a caspase-dependent apoptosis versus either drug alone. The Cancer Genome Atlas (TCGA) transcriptomic dataset revealed overexpression of CDK1 in human colorectal cancers versus normal colon. Together, these data establish CDK1 as a novel mediator of apoptosis resistance in colorectal cancers whose combined targeting with a MEK/ERK inhibitor represents an effective therapeutic strategy. CDK1 is a novel mediator of apoptosis resistance in colorectal cancers whose dual targeting with a MEK inhibitor may be therapeutically effective..

Genome-wide association analysis in tetraploid wheat revealed novel and diverse loci for seedling and field resistance to stripe rust in elite spring durum wheat accessions from worldwide. Improving resistance to stripe rust, caused by Puccinia striiformis f. sp. tritici, is a major objective for wheat breeding. To identify effective stripe rust resistance loci, a genome-wide association study (GWAS) was conducted using 232 elite durum wheat (Triticum turgidum ssp. durum) lines from worldwide breeding programs. Genotyping with the 90 K iSelect wheat single nucleotide polymorphism (SNP) array resulted in 11,635 markers distributed across the genome. Response to stripe rust infection at the seedling stage revealed resistant and susceptible accessions present in rather balanced frequencies for the six tested races, with a higher frequency of susceptible responses to United States races as compared to Italian races (61.1 vs. 43.1% of susceptible accessions). Resistance at the seedling stage only partially explained adult plant resistance, which was found to be more frequent with 67.7% of accessions resistant across six nurseries in the United States. GWAS identified 82 loci associated with seedling stripe rust resistance, five of which were significant at the false discovery rate adjusted P value <0.1 and 11 loci were detected for the field response at the adult plant stages in at least two environments. Notably, Yrdurum-1BS.1 showed the largest effect for both seedling and field resistance, and is therefore considered as a major locus for resistance in tetraploid wheat. Our GWAS study is the first of its kind for stripe rust resistance in tetraploid wheat and provides an overview of resistance in elite germplasm and reports new loci that can be used in breeding resistant cultivars.