Generation of an inducible mouse model to reversibly silence Stat3.

Signal transducer and activator of transcription 3 (Stat3) is a transcription factor that has many essential roles during inflammation, development and cancer. Stat3 is therefore an attractive therapeutic target in many diseases. While current Stat3 knockout mouse models led to a better understanding of the role of Stat3, the irreversible nature of Stat3 ablation does not model the effects of transient Stat3 therapeutic inhibition, and does not inform on potential dosage effects of Stat3. Using RNAi technology, we have generated a new mouse model allowing the inducible and reversible silencing of Stat3 in vivo, which mirrors the effects of specific Stat3 therapeutic interference. We showed that upon Doxycycline-mediated activation of the Stat3 short-hairpin RNA, Stat3 expression was efficiently reduced by about 80% in multiple organs and cell types. Moreover, Stat3 reduction was sufficient to reduce tumor burden in a clinically-validated mouse model of gastric cancer. Finally, we demonstrated that Stat3 silencing during embryonic development led to reduced birth rate without leading to complete embryonic lethality, in contrast to full Stat3 ablation. In conclusion, this new mouse model will be invaluable to understand the effects of Stat3 therapeutic interference and Stat3 dosage effects.

Resolving the slip-rate inconsistency of the northern Dead Sea fault.

Reported fault slip rates, a key quantity for earthquake hazard and risk analyses, have been inconsistent for the northern Dead Sea fault (DSF). Studies of offset geological and archeological structures suggest a slip rate of 4 to 6 millimeters per year, consistent with the southern DSF, whereas geodetic slip-rate estimates are only 2 to 3 millimeters per year. To resolve this inconsistency and overcome limited access to the northern DSF in Syria, we here use burst-overlap interferometric time-series analysis of satellite radar images to provide an independent slip-rate estimate of ~2.8 millimeters per year. We also show that the high geologic slip rate could, by chance, be inflated by earthquake clustering and suggest that the slip-rate decrease from the southern to northern DSF can be explained by splay faults and diffuse offshore deformation. These results suggest a microplate west of the northern DSF and a lower earthquake hazard for that part of the fault.

High-resolution co-seismic fault offsets of the 2023 Türkiye earthquake ruptures using satellite imagery.

On February 6, 2023, southern Türkiye was struck by two large earthquakes at 01:17 UTC (Mw=7.8, Pazarcik, Kahramanmaras) and 10:30 UTC (Mw = 7.6, Elbistan, Kahramanmaras), causing severe damage at the complex junction of the Dead Sea Fault (DSF), the Cyprus Arc and the East Anatolian Fault Zone (EAFZ). The ruptures propagated along several known strands of the southwestern termination of the EAFZ, the main Pazarcik and Karasu valley faults, and the Çardak-Sürgü fault. Here we present the high-resolution mapping of the entire coseismic surface rupture and an estimate of the rupture width, total and on-fault offset, and diffuse deformation obtained a few days to three months after the two mainshocks. The mapping is derived from image correlation of Sentinel-2 optical satellite imagery and validated with offset measurements collected on the ground. We find that the ruptures extend over lengths of 310 km and 140 km for the Mw 7.8 and Mw 7.6 mainshocks, respectively. The maximum offsets reach 7.5 ± 0.8 m and 8.7 ± 0.8 m near the epicenters of the Mw 7.8 and Mw 7.6 events, respectively. We propose a segmentation of the two ruptures based on these observations, and further discuss the location of the potential supershear rupture. The use of optical image correlation, complemented by field investigations along earthquake faults, provides new insights into seismic hazard assessment.