Rapid mechanosensitive migration and dispersal of newly divided mesenchymal cells aid their recruitment into dermal condensates.

Embryonic mesenchymal cells are dispersed within an extracellular matrix but can coalesce to form condensates with key developmental roles. Cells within condensates undergo fate and morphological changes and induce cell fate changes in nearby epithelia to produce structures including hair follicles, feathers, or intestinal villi. Here, by imaging mouse and chicken embryonic skin, we find that mesenchymal cells undergo much of their dispersal in early interphase, in a stereotyped process of displacement driven by 3 hours of rapid and persistent migration followed by a long period of low motility. The cell division plane and the elevated migration speed and persistence of newly born mesenchymal cells are mechanosensitive, aligning with tissue tension, and are reliant on active WNT secretion. This behaviour disperses mesenchymal cells and allows daughters of recent divisions to travel long distances to enter dermal condensates, demonstrating an unanticipated effect of cell cycle subphase on core mesenchymal behaviour.

Feather arrays are patterned by interacting signalling and cell density waves.

Feathers are arranged in a precise pattern in avian skin. They first arise during development in a row along the dorsal midline, with rows of new feather buds added sequentially in a spreading wave. We show that the patterning of feathers relies on coupled fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) signalling together with mesenchymal cell movement, acting in a coordinated reaction-diffusion-taxis system. This periodic patterning system is partly mechanochemical, with mechanical-chemical integration occurring through a positive feedback loop centred on FGF20, which induces cell aggregation, mechanically compressing the epidermis to rapidly intensify FGF20 expression. The travelling wave of feather formation is imposed by expanding expression of Ectodysplasin A (EDA), which initiates the expression of FGF20. The EDA wave spreads across a mesenchymal cell density gradient, triggering pattern formation by lowering the threshold of mesenchymal cells required to begin to form a feather bud. These waves, and the precise arrangement of feather primordia, are lost in the flightless emu and ostrich, though via different developmental routes. The ostrich retains the tract arrangement characteristic of birds in general but lays down feather primordia without a wave, akin to the process of hair follicle formation in mammalian embryos. The embryonic emu skin lacks sufficient cells to enact feather formation, causing failure of tract formation, and instead the entire skin gains feather primordia through a later process. This work shows that a reaction-diffusion-taxis system, integrated with mechanical processes, generates the feather array. In flighted birds, the key role of the EDA/Ectodysplasin A receptor (EDAR) pathway in vertebrate skin patterning has been recast to activate this process in a quasi-1-dimensional manner, imposing highly ordered pattern formation.

A pilot study to assess the utility of five established variables to standardize exercise treadmill test reporting.

BACKGROUND: The prognostic utility of 5 established variables (functional capacity, Duke treadmill score, chronotropic response to exercise, heart rate recovery, and premature ventricular contractions) together after routine exercise treadmill testing (ETT) has not been determined. METHODS: We assessed the combined prognostic ability of 5 established variables for the primary outcome (myocardial infarction [MI], coronary revascularization [CR] or all-cause mortality) and the secondary outcome of unnecessary downstream testing (defined as receipt of further noninvasive imaging without CR, MI, or death) compared with standard methods. Using a retrospective study design, 1857 consecutive patients were enrolled in the year 2014 and followed until December 31, 2015. Optimal discrimination and global fit statistics were assessed from logistic regression models. Classification and regression tree (CART) methodology was used for the final model. RESULTS: The mean [SD] age was 56.0 [12.5]years; median comorbidities (2, IQR 2) with 26% having an equivocal report. Compared to other models, a model with age, sex, and the 5 established variables showed an improvement in discrimination for the primary [c-statistic 0.85 versus (0.69-0.79)] and secondary [c-statistic 0.73 versus (0.65-0.71)] outcomes with substantial improvement in global fit. The final, optimal, 10-fold cross-validated CART model had a c-statistic of 0.78. CONCLUSIONS: The utility of the 5-established variables, based on the current study, resides in its ability to decrease unnecessary downstream testing and improve cardiovascular event prognostication. This is accomplished by removing the subjective interpretation of currently used ETT variables that can lead to an equivocal report.