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Schäfer, B.

Publications and source records attributed to Schäfer, B..

3 recordsLinked to original sources

p53 isoforms have a high aggregation propensity, interact with chaperones and lack binding to p53 interaction partners

The p53 transcription factor family consists of the three members p53, p63 and p73. Both p63 and p73 exist in different isoforms that are well characterized. Isoforms have also been identified for p53 and it has been proposed that they are responsible for increased cancer metastasis. In contrast to the p63 and p73 isoforms, which do not contain truncations in folded domains, most of the p53 isoforms contain only parts of either the DNA binding domain or the oligomerization domain. To better understand the effect of p53 isoforms in cancer we provide here a comprehensive biochemical characterization. With the exception of the {Delta}40p53 isoform none of the other variants can bind to DNA with high affinity and none can upregulate transcription. Probing with antibodies, DARPins and other interaction partners confirmed that isoforms harboring deletions in the DNA binding domain cannot interact specifically with them, but instead are bound to chaperones and other factors known to interact with misfolded proteins. Expression of isoforms with deletions in the DNA binding domain results in upregulation of cellular chaperones. If the expression level surpasses a threshold, the chaperone system can no longer keep these isoforms soluble resulting in aggregation and co-aggregation with other factors.

biophysics↗

Phylogenetic analysis of pathogenic and non-pathogenic Trichoderma isolates from plants, soil and commercial bio products Short titel: Phylogenetic analysis of pathogenic and non-pathogenic Trichoderma isolates

Fungi of the genus Trichoderma are found worldwide in various types of soil, plant rhizospheres, and plant materials. Several Trichoderma spp. are used in crop health management to promote growth and control plant diseases. Although widely considered beneficial, some members have been reported to be pathogenic to maize, causing a disease called Trichoderma ear rot. Since 2018, T. afroharzianum has caused significant infections of maize cobs in Germany, France and Italy. This study aimed to investigate the pathogenicity and phylogenetic relationships among different Trichoderma strains from diverse sources and geographical origins. Species identification and phylogenetic analysis were performed by sequencing internal transcribed spacer (ITS), translation elongation factor 1- (TEF1-) and RNA polymerase II subunit B (RBP2) genes, and pathogenicity was tested by artificially inoculating maize cobs under controlled greenhouse conditions. A total of 131 isolates were analyzed and assigned to 20 Trichoderma species. Among these, 39 isolates from six species were pathogenic, causing symptoms of green spore layers between kernels and husk leaves. While previous studies primarily identified T. afroharzianum as the main species causing Trichoderma ear rot, this study found that isolates of T. asperellum, T. atroviride and T. guizhouense also exhibit pathogenicity on maize cobs. Additionally, Trichoderma strains from commercial biocontrol products displayed unexpected pathogenicity inducing up to 92% disease severity on maize cobs. Most T. afroharzianum strains induced high levels of disease severity, although some isolates of the same species did not cause any disease, indicating a large heterogeneity in pathogenicity within the species. Notably, phylogeny reconstruction based on the TEF1- and RBP2 genes, did not result in any discernible clustering between pathogenic and non-pathogenic isolates. A further novel finding is the isolation of pathogenic Trichoderma isolates from soil, demonstrating that soil can serve as a reservoir for pathogenic species. This study highlights the need for careful selection and monitoring of Trichoderma strains for agricultural use, considering their beneficial and pathogenic potential. Author SummaryIn this study, we explored the ability of different Trichoderma species to infect maize plants. Trichoderma is a group of fungi known for its beneficial role in agriculture, often used as a biological pesticide to control fungal plant diseases. However, some species within this group can also act as pathogens, causing infections in crops like maize. We found that one species, T. afroharzianum, is particularly aggressive, capable of infecting maize without the plant being wounded first. This makes it a potentially serious threat to crop health. In contrast, other species, such as T. atroviride and T. asperellum, only caused infections when the maize was already damaged. Our research suggests that pathogenic Trichoderma species not only effectively infect plants but can also survive well in soil, making their control difficult. These findings highlight the need for better understanding of how these fungi operate in order to manage the risks they pose to important crops like maize, while still taking advantage of their beneficial uses in agriculture.

microbiology↗

Elimusertib outperforms standard of care chemotherapy in preclinical patient-derived pediatric solid tumor models

The small molecule inhibitor of ataxia telangiectasia and Rad3-related protein (ATR), elimusertib, is currently being tested clinically in various cancer entities in adults and children. Its preclinical anti-tumor activity in pediatric malignancies, however, is largely unknown. We here assessed the preclinical activity of elimusertib in >40 cell lines and >30 patient-derived xenograft (PDX) models derived from common pediatric solid tumor entities. Detailed in vitro and in vivo molecular characterization of the treated models enabled the evaluation of response biomarkers. Pronounced objective response rates were observed for elimusertib monotherapy in PDX, when treated with a regimen currently used in clinical trials. Strikingly, elimusertib outperformed standard of care chemotherapies, particularly in alveolar rhabdomysarcoma PDX. Thus, elimusertib has strong preclinical anti-tumor activity in pediatric solid tumor models, which may translate to clinically meaningful responses in patients. Statement of translational relevanceElimusertib is a small molecule inhibitor of ATR. ATR inhibitors have shown promising results as anticancer agents in adult cancers, but there is limited information on their effectiveness in pediatric solid tumors. Using a cohort of 32 patient-derived xenografts from pediatric solid tumors, we here evaluated the therapeutic potential of elimusertib in vivo. Elimusertib reduced tumor volume growth in all samples. Elimusertib had very limited toxicity and was potent even in tumors with preexisting chemoresistance. Our preclinical data indicates that elimusertib is a safe and potent therapeutic option for pediatric solid tumors. This data may serve as a rationale for the development of pediatric clinical trials for ATR inhibitors.

cancer biology↗