The Regulatory Mechanism of Transthyretin Irreversible Aggregation through Liquid-to-Solid Phase Transition.

Transthyretin (TTR) aggregation and amyloid formation are associated with several ATTR diseases, such as senile systemic amyloidosis (SSA) and familial amyloid polyneuropathy (FAP). However, the mechanism that triggers the initial pathologic aggregation process of TTR remains largely elusive. Lately, increasing evidence has suggested that many proteins associated with neurodegenerative diseases undergo liquid-liquid phase separation (LLPS) and subsequent liquid-to-solid phase transition before the formation of amyloid fibrils. Here, we demonstrate that electrostatic interactions mediate LLPS of TTR, followed by a liquid-solid phase transition, and eventually the formation of amyloid fibrils under a mildly acidic pH in vitro. Furthermore, pathogenic mutations (V30M, R34T, and K35T) of TTR and heparin promote the process of phase transition and facilitate the formation of fibrillar aggregates. In addition, S-cysteinylation, which is a kind of post-translational modification of TTR, reduces the kinetic stability of TTR and increases the propensity for aggregation, while another modification, S-sulfonation, stabilizes the TTR tetramer and reduces the aggregation rate. Once TTR was S-cysteinylated or S-sulfonated, they dramatically underwent the process of phase transition, providing a foundation for post-translational modifications that could modulate TTR LLPS in the context of pathological interactions. These novel findings reveal molecular insights into the mechanism of TTR from initial LLPS and subsequent liquid-to-solid phase transition to amyloid fibrils, providing a new dimension for ATTR therapy.

[Value of long-distance fetal heart rate monitoring on the pre-partum health care of the pregnant woman with umbilical cord loops].

OBJECTIVE: To explore the value of the long-distance fetal heart rate (FHR) monitoring on the pre-partum health care of self-monitoring at home for pregnant woman with the umbilical cord loops. METHODS: The umbilical cord loops was diagnosed by ultrasonography. In the study group, 896 pregnant women with the umbilical cord loops accepted long-distance FHR monitoring and the count of fetal movement (FM) as family-self monitoring methods, while in the control group, 1 914 pregnant women with the umbilical cord loops used the count of FM only as family-self monitoring method. Abnormal non-stress test (NST), variable deceleration, fetal distress, neonate asphyxia, fetal death, stillbirth, operative delivery rate were analyzed between the study and control group retrospectively. RESULTS: The incidence of NST reactive pattern and non- reactive pattern and the variable deceleration in long-distance FHR monitoring of the study group were significantly higher than those in routine FHR monitoring. The incidence of fetal distress in the study group (35.0%) was significantly higher than that in the control group (30.9%), while the incidence of neonatal asphyxia in the study group (3.5%) was significantly lower than that in the control group (5.6%). The incidence of outside hospital fetal death in the study group (0.1%) was significantly lower than that in the control group (0.8%). There were no significant differences of cesarean section rate, forceps or vacuum extractor delivery between the two groups (P > 0.05). CONCLUSIONS: This study suggested that the high variable rate in the long-distance FHR monitoring curve was related to the incidence of the fetal distress. It didn't increase the cesarean section rate and vaginal operative delivery rate, but decreased the neonatal asphyxia and outside hospital fetal death rate. The long-distance FHR monitoring combined with the count of FM may be a better family-self monitoring method for the pregnant women with the umbilical cord loops.