breast cancer ͉ DNA damage response ͉ medullary carcinoma

Botrytis cinerea is a necrotrophic fungus that infects a wide range of fruit, vegetable and flower crops. Penetration of the host cuticle occurs via infection structures that are formed in response to appropriate plant surface signals. The differentiation of these structures requires a highly conserved mitogen-activated protein (MAP) kinase cascade including the MAP kinase BMP1. In yeast and several plant-pathogenic fungi, the signalling mucin Msb2 has been shown to be involved in surface recognition and MAP kinase activation. In this study, a B. cinerea msb2 mutant was generated and characterized. The mutant showed normal growth, sporulation, sclerotia formation and stress resistance. In the absence of nutrients, abnormal germination with multiple germ tubes was observed. In the presence of sugars, normal germination occurred, but msb2 germlings were almost unable to form appressoria or infection cushions on hard surfaces. Nevertheless, the msb2 mutant showed only a moderate delay in lesion formation on different host plants, and formed expanding lesions similar to the wild-type. Although the wild-type showed increasing BMP1 phosphorylation during the first hours of germination on hard surfaces, the phosphorylation levels in the msb2 mutant were strongly reduced. Several genes encoding secreted proteins were found to be co-regulated by BMP1 and Msb2 during germination. Taken together, B. cinerea Msb2 is likely to represent a hard surface sensor of germlings and hyphae that triggers infection structure formation via the activation of the BMP1 MAP kinase pathway.

Correct spatial and temporal control of cell proliferation is of fundamental importance for tissue homeostasis. Its deregulation has been associated with several pathological conditions. In common with almost every aspect of plant and animal biology, cell proliferation is dominated by day-night rhythms generated by the circadian clock. However, our understanding of the crosstalk between the core clock and cell cycle control mechanisms remains incomplete. In this study, using zebrafish as a vertebrate model system, we show that the nuclear localization of the Y-box binding protein 1 (YB-1), a regulator of cyclin expression and a hallmark of certain cancers, is robustly regulated by the circadian clock. We implicate clock-controlled changes in YB-1 SUMOylation as one of the mechanisms regulating its periodic nuclear entry at the beginning of the light phase. Furthermore, we demonstrate that YB-1 nuclear protein is able to downregulate cyclin A2 mRNA expression in zebrafish via its direct interaction with the cyclin A2 promoter. Thus, by acting as a direct target of cyclic posttranslational regulatory mechanisms, YB-1 serves as one bridge between the circadian clock and its cell cycle control.

The demographics of donor and recipient candidates for kidney transplantation (KT) have substantially changed. Recipients tend to be older and polymorbid and KT to marginal recipients is associated with delayed graft function (DGF), prolonged hospitalization, inferior long-term allograft function, and poorer patient survival. In parallel, donors are also older, suffer from several comorbidities, and donations coming from circulatory death (DCD) predominate, which in turn leads to early and late complications. However, it is unclear how donor and recipient risk factors interact. In this retrospective cohort study, we assess the overall and combined impact of a KT from marginal donors to marginal recipients. We focused on: 1) DGF; 2) hospital stay and number of dialysis days after KT and 3) allograft function at 6 months. Among the 369 KT included, the overall DGF rate was 25% (n = 92) and median time from reperfusion to DGF resolution was 7.8 days (IQR: 3.0-13.8 days). Overall, patients received four dialysis sessions (IQR: 2-8). The combination of pre-KT anuria (< 200 ml/24h, 32%) and DCD procurement (14%) was significantly associated with DGF, length of hospital stay, and severe perioperative complications, predominantly in recipients 50 years and older.