Progressive lung fibrosis is associated with poorly understood aging-related endothelial cell dysfunction. To gain insight into endothelial cell alterations in lung fibrosis we performed single cell RNA-sequencing of bleomycin-injured lungs from young and aged mice. Analysis reveals activated cell states enriched for hypoxia, glycolysis and YAP/TAZ activity in ACKR1+ venous and TrkB+ capillary endothelial cells. Endothelial cell activation is prevalent in lungs of aged mice and can also be detected in human fibrotic lungs. Longitudinal single cell RNA-sequencing combined with lineage tracing demonstrate that endothelial activation resolves in young mouse lungs but persists in aged ones, indicating a failure of the aged vasculature to return to quiescence. Genes associated with activated lung endothelial cells states in vivo can be induced in vitro by activating YAP/TAZ. YAP/TAZ also cooperate with BDNF, a TrkB ligand that is reduced in fibrotic lungs, to promote capillary morphogenesis. These findings offer insights into aging-related lung endothelial cell dysfunction that may contribute to defective lung injury repair and persistent fibrosis.

Understanding the dynamic pathogenesis and treatment response in pulmonary diseases requires probing the lung at cellular resolution in real time. Despite advances in intravital imaging, optical imaging of the lung during active respiration and circulation has remained challenging. Here, we introduce the crystal ribcage: a transparent ribcage that allows multiscale optical imaging of the functioning lung from whole-organ to single-cell level. It enables the modulation of lung biophysics and immunity through intravascular, intrapulmonary, intraparenchymal and optogenetic interventions, and it preserves the three-dimensional architecture, air–liquid interface, cellular diversity and respiratory–circulatory functions of the lung. Utilizing these capabilities on murine models of pulmonary pathologies we probed remodeling of respiratory–circulatory functions at the single-alveolus and capillary levels during disease progression. The crystal ribcage and its broad applications presented here will facilitate further studies of nearly any pulmonary disease as well as lead to the identification of new targets for treatment strategies.

In relation to its rapid infrastructure expansion, exemplified by projects like the Najran Valley Dam or the rehabilitation of agricultural terraces, Saudi Arabia stands out among the Arabian Gulf nations. To mitigate the earthquake-related risks effectively, it is imperative to conduct an exhaustive analysis of its natural hazards. The southwesternmost region of Saudi Arabia is the main subject area of this study for the probabilistic seismic hazard assessment (PSHA), which aims to identify the peak ground acceleration (PGA) and spectral acceleration (SA) values. The investigation encompasses a 10% and 5% probability of occurrence over a 50-year exposure time for both B/C and C NEHRP soils. In order to take into account the earthquake activity that takes place in the vicinity of the Red Sea Rift, which in fact may have an impact on the seismic hazard in this active tectonic region, different seismic source zones were especially designed for this evaluation. Various characteristics such as the uncertainties related to the b-value, the expected maximum magnitude, and different ground motion prediction equations (GMPEs) were integrated using a logic tree scheme. Additionally, regression relationships between the computed ground motion values were established, and a novel design response spectrum was developed and recommended for several cities. Regarding the key findings, it is significant to highlight that the seismic hazard decreases towards the northeast, when moving away from the Red Sea Rift, confirming anticipated trends where proximity to the rift corresponds to increased seismic hazard. Notably, cities such as Farasan Island, Jazan, Al Qunfundhah, Al Lith and Al Birk present the highest observed hazard values among all the cities analyzed. For these cities, the obtained maximum SA values for both 475 and 975 years under B/C site conditions are as follows: 0.268 g and 0.412 g, 0.121 g and 0.167 g, 0.099 g and 0.150 g, 0.083 g and 0.135 g, and 0.066 g and 0.118 g, respectively. These results emphasize the crucial necessity of adequately evaluating and thoroughly updating the seismic hazard inherent to these particular areas to enhance the risk reduction and disaster readiness initiatives.