Evaluation of Wheat Resistance to Snow Mold Caused by Microdochium nivale (Fr) Samuels and I.C. Hallett under Abiotic Stress Influence in the Central Non-Black Earth Region of Russia

Microdochium nivale is one of the most harmful fungal diseases, causing colossal yield losses and deteriorating grain quality. Wheat genotypes from the world collection of the N.I. Vavilov Institute (VIR) were evaluated for fifty years to investigate their resistance to biotic stress factors (M. nivale). Between 350 to 1085 of winter wheat genotypes were investigated annually. Ten out of fifty years were identified as rot epiphytotics (1978, 1986, 1989, 1990, 1993, 1998, 2001, 2003, 2005 and 2021). The wheat collection was investigated by following the VIR methodological requirements and CMEA unified classification of Triticum aestivum L. The field investigations were carried out in the early spring during fixed-route observations and data collection was included on the spread and development degree of the disease, followed by microbiological and microscopic pathogen identifications. The observations revealed that the primary reason for pink snow mold to infect the wheat crops was abiotic stress factors, such as thawed soil covered in snow that increased the soil temperature by 1.0–4.6 °C above normal. Under these conditions, the plants kept growing, quickly exhausting their carbohydrate and protein resources, thus weakening their immune systems, which made them an easy target for different infections, mainly cryophilic fungi, predominantly Microdochium nivale in the Moscow region. In some years, the joint effect of abiotic and biotic stresses caused crop failure, warranting the replanting of the spring wheat. The investigated wheat genotypes exhibited variable resistance to pink snow mold. The genotypes Mironovskaya 808 (k-43920) from Ukraine;l Nemchinovskaya 846 (k-56861), from Russia; Novobanatka (k-51761) from Yugoslavia; Liwilla (k-57580) from Poland; Zdar (UH 7050) from the Czech Republic; Maris Plowman (k-57944) from the United Kingdom; Pokal (k-56827) from Austria; Hvede Sarah (k-56289) from Denmark; Moldova 83 (k-59750) from Romania; Compal (k-57585) from Germany; Linna (k-45889) from Finland and Kehra (k-34228) from Estonia determined the sources, stability and tolerance to be used in advanced breeding programs

Inhibition of GATA2 in prostate cancer by a clinically available small molecule.

Castration-resistant prostate cancer (CRPC) remains highly lethal and in need of novel, actionable therapeutic targets. The pioneer factor GATA2 is a significant prostate cancer (PC) driver and is linked to poor prognosis. GATA2 directly promotes androgen receptor (AR) gene expression (both full-length and splice-variant) and facilitates AR binding to chromatin, recruitment of coregulators, and target gene transcription. Unfortunately, there is no clinically applicable GATA2 inhibitor available at the moment. Using a bioinformatics algorithm, we screened in silico 2650 clinically relevant drugs for a potential GATA2 inhibitor. Validation studies used cytotoxicity and proliferation assays, global gene expression analysis, RT-qPCR, reporter assay, reverse phase protein array analysis (RPPA), and immunoblotting. We examined target engagement via cellular thermal shift assay (CETSA), ChIP-qPCR, and GATA2 DNA-binding assay. We identified the vasodilator dilazep as a potential GATA2 inhibitor and confirmed on-target activity via CETSA. Dilazep exerted anticancer activity across a broad panel of GATA2-dependent PC cell lines in vitro and in a PDX model in vivo. Dilazep inhibited GATA2 recruitment to chromatin and suppressed the cell-cycle program, transcriptional programs driven by GATA2, AR, and c-MYC, and the expression of several oncogenic drivers, including AR, c-MYC, FOXM1, CENPF, EZH2, UBE2C, and RRM2, as well as of several mediators of metastasis, DNA damage repair, and stemness. In conclusion, we provide, via an extensive compendium of methodologies, proof-of-principle that a small molecule can inhibit GATA2 function and suppress its downstream AR, c-MYC, and other PC-driving effectors. We propose GATA2 as a therapeutic target in CRPC