Snail induces epithelial cell extrusion by regulating RhoA contractile signalling and cell-matrix adhesion.

Cell extrusion is a morphogenetic process that is implicated in epithelial homeostasis and elicited by stimuli ranging from apoptosis to oncogenic transformation. To explore whether the morphogenetic transcription factor Snail (SNAI1) induces extrusion, we inducibly expressed a stabilized Snail6SA transgene in confluent MCF-7 monolayers. When expressed in small clusters (less than three cells) within otherwise wild-type confluent monolayers, Snail6SA expression induced apical cell extrusion. In contrast, larger clusters or homogenous cultures of Snail6SA cells did not show enhanced apical extrusion, but eventually displayed sporadic basal delamination. Transcriptomic profiling revealed that Snail6SA did not substantively alter the balance of epithelial and mesenchymal genes. However, we identified a transcriptional network that led to upregulated RhoA signalling and cortical contractility in cells expressing Snail6SA Enhanced contractility was necessary, but not sufficient, to drive extrusion, suggesting that Snail collaborates with other factors. Indeed, we found that the transcriptional downregulation of cell-matrix adhesion cooperates with contractility to mediate basal delamination. This provides a pathway for Snail to influence epithelial morphogenesis independently of classic epithelial-to-mesenchymal transition.

The impact of electric scooters in Melbourne: data from a major trauma service.

BACKGROUND: The proliferation of electric scooters globally has been associated with an increase in related injuries and consequent economic burden. This study aims to assess the injury patterns and the economic impact associated with electric scooter use in Melbourne, Australia. METHODS: A retrospective cohort study was conducted using hospital and registry data from January 2022 to January 2023. Data collected included demographic details, alcohol and helmet use, injury type and severity, operative treatment provided, and direct medical costs. The economic impact (in AUD) of the patient's emergency presentation and hospital admission was calculated. RESULTS: During the study period, 256 electric scooter related injuries were recorded, comprising 247 riders and nine pedestrians. The majority of patients were males (69%) with a median age of 29.5 (15-78). Alcohol use was reported by 34% and helmet use by 33%. Injuries most commonly affected the upper limb (53%) and head (50%), with abrasions (75%) and fractures (48%) being the most common type of injury sustained. The total hospital cost was $1 911 062, and the median cost was $1321.66 per patient (IQR: $479.37-$5096.65). CONCLUSION: Electric scooter usage, as observed through patient presentations to the Royal Melbourne Hospital, is associated with a considerable number of injuries, primarily among young males, and an ensuing substantial economic burden. The findings underscore the urgent need for improved safety measures to minimize electric scooter-related injuries and their clinical and economic repercussions.

Anillin Promotes Cell Contractility by Cyclic Resetting of RhoA Residence Kinetics.

RhoA stimulates cell contractility by recruiting downstream effectors to the cortical plasma membrane. We now show that direct binding by anillin is required for effective signaling: this antagonizes the otherwise labile membrane association of GTP-RhoA to promote effector recruitment. However, since its binding to RhoA blocks access by other effectors, we demonstrate that anillin must also concentrate membrane phosphoinositide-4,5-P2 (PIP2) to promote signaling. We propose and test a sequential pathway where GTP-RhoA first binds to anillin and then is retained at the membrane by PIP2 after it disengages from anillin. Importantly, re-binding of membrane GTP-RhoA to anillin, regulated by the cortical density of anillin, creates cycles through this pathway. These cycles repeatedly reset the dissociation kinetics of GTP-RhoA, substantially increasing its dwell time to recruit effectors. Thus, anillin regulates RhoA signaling by a paradigm of kinetic scaffolding that may apply to other signals whose efficacy depends on their cortical dwell times.