Notch signalling pathway is central to development of metazoans. The pathway codes a binary fate switch. Upon activation, downstream signals contribute to resolution of fate dichotomies such as proliferation/differentiation or sub-lineage differentiation outcome. There is, however, an interesting paradox in the Notch signalling pathway. Despite remarkable predictability of fate outcomes instructed by the Notch pathway, the associated transcriptome is versatile and plastic. This inconsistency suggests the presence of an interface that compiles input from the plastic transcriptome of the Notch pathway but communicates only a binary output in biological decisions. Herein, we address the interface that determines fate outcomes. We provide an alternative hypothesis for the Notch pathway as a biological master switch that operates by induction of genetic noise and bistability in order to facilitate resolution of dichotomous fate outcomes in development.Graphical abstract

A core imprint of metazoan life is that perturbations of cell cycle are offset by compensatory changes in successive cellular generations. This trait enhances robustness of multicellular growth and requires transmission of signaling cues within a cell lineage. Notably, the identity and mode of activity of transgenerational signals remain largely unknown. Here we report the discovery of a natural antisense transcript encoded in exon 25 of notch-1 locus (nAS25) by which mother cells control the fate of notch-1 transcript in daughter cells to buffer against perturbations of cell cycle. The antisense transcript is transcribed at G1 phase of cell cycle from a bi-directional E2F1-dependent promoter in the mother cell where the titer of nAS25 is calibrated to the length of G1. Transmission of the antisense transcript from mother to daughter cells stabilizes notch-1 sense transcript in G0 phase of daughter cells by masking it from RNA editing and resultant nonsense-mediated degradation. In consequence, nAS25-mediated amplification of notch-1 signaling reprograms G1 phase in daughter cells to compensate for the altered dynamics of the mother cell. The function of nAS25/notch-1 in integrating G1 phase history of the mother cell into that of daughter cells is compatible with the predicted activity of a molecular oscillator, slower than cyclins, that coordinates cell cycle within cell lineage.

Highlights d During neurulation, neuroepithelial cells cannibalize yolk sac erythroblasts d Heme from cannibalized erythroblasts triggers precocious neuronal differentiation d Heme-mediated activation of mitochondria is key to acceleration of neurogenesis Authors S x€ ukran Ö zsoy,

Penile cancer is a rare cancer, with the majority treated with penile preserving methods.There remains a role for partial and totally penectomy for advanced and more proximal penile cancers.Significant functional and psychological morbidity can ensue for patients undergoing surgical management.Recent studies and guidelines are changing the way Urologists approach surgical management of penile malignancies. Reductions in safe surgical margin recommendations from 2 cm to 3-5 mm provide surgeons with the ability to perform penile preserving techniques to maximise patient functionality. These guidelines are reflected by recent studies showing that smaller surgical margins; although heralding higher rates of local recurrence, have no detriment on cancer specific or overall survival rate. Although oncological clearance remains the primary outcome for surgical management of penile cancer, the ability to perform radical salvage surgery at a later date means patients are more likely to experience a longer period of functionality without sacrificing oncologic outcomes. The importance of patient education on regular self-examination as well as clinic follow up are key in identifying local recurrence and planning salvage surgery if needed to maintain oncologic control. Ongoing studies into the functional and psychological outcomes of patients undergoing partial penectomy show encouraging results however further studies are needed to elucidate long-term outcomes. The evolving paradigm of surgical management in penile malignancy is shifting to favour organ preserving techniques in order to maximise functional, psychological and aesthetic outcomes without compromising patients' oncologic outcomes-however a role still exists for radical surgery in advanced penile malignancy.