RIPK1 is a master regulator of inflammatory signaling and cell death and increased RIPK1 activity is observed in human diseases, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis... Show moreRIPK1 is a master regulator of inflammatory signaling and cell death and increased RIPK1 activity is observed in human diseases, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). RIPK1 inhibition has been shown to protect against cell death in a range of preclinical cellular and animal models of diseases. SAR443060 (previously DNL747) is a selective, orally bioavailable, central nervous system (CNS)-penetrant, small-molecule, reversible inhibitor of RIPK1. In three early-stage clinical trials in healthy subjects and patients with AD or ALS (NCT03757325 and NCT03757351), SAR443060 distributed into the cerebrospinal fluid (CSF) after oral administration and demonstrated robust peripheral target engagement as measured by a reduction in phosphorylation of RIPK1 at serine 166 (pRIPK1) in human peripheral blood mononuclear cells compared to baseline. RIPK1 inhibition was generally safe and well-tolerated in healthy volunteers and patients with AD or ALS. Taken together, the distribution into the CSF after oral administration, the peripheral proof-of-mechanism, and the safety profile of RIPK1 inhibition to date, suggest that therapeutic modulation of RIPK1 in the CNS is possible, conferring potential therapeutic promise for AD and ALS, as well as other neurodegenerative conditions. However, SAR443060 development was discontinued due to long-term nonclinical toxicology findings, although these nonclinical toxicology signals were not observed in the short duration dosing in any of the three early-stage clinical trials. The dose-limiting toxicities observed for SAR443060 preclinically have not been reported for other RIPK1-inhibitors, suggesting that these toxicities are compound-specific (related to SAR443060) rather than RIPK1 pathway-specific. Show less
Xia, X.; Pan, Y.; Chang, M.; Wu, D.; Zhang, X.; Xia, J.; Song, K. 2022
Temperature affects leaf lifespan (LL) across either space or time, driving long-term adaptation and short-term thermal acclimation, respectively. However, a comprehensive understanding of the... Show moreTemperature affects leaf lifespan (LL) across either space or time, driving long-term adaptation and short-term thermal acclimation, respectively. However, a comprehensive understanding of the phenomenon and the underlying phenological mechanisms remain poorly understood. The present study investigated the relationship between LL and temperature in six common deciduous trees across both spatial and temporal gradients, then explained the LL variation patterns based on phenological shifts. Using long-term (1971–2000) phenological records of six deciduous tree species at 54 sites across central Europe, we analyzed spatial and temporal variations of LL and leaf phenology along temperature gradients. We assessed the relative contribution of phenological shifts to LL variations by comparing absolute changes in leaf-out and leaf fall. We reported positive LL-temperature relationships across all observations along both spatial (+3.32 days/°C) and temporal (+4.43 days/°C) gradients. The paired t-test of the six deciduous tree species showed no significant difference in regression slopes of LL- temperature between the two gradients (t = −1.50, df = 5, P = 0.194). Prolonged LL can be explained mainly by earlier leaf-out induced by warmer temperatures both spatially (−3.22 days/°C) and temporally (−4.08 days/°C). The converging temperature-dependent patterns of LL across time and space indicate that short-term thermal acclimation keeps pace with long-term genetic adaptation for deciduous trees in Europe. Earlier leaf-out is the key force shaping the LL-temperature relationship. These results provide insights for predicting future vegetation dynamics under global warming. Show less
Huisman, M.V.; Rothman, K.J.; Paquette, M.; Teutsch, C.; Diener, H.C.; Dubner, S.J.; ... ; Frappe, T 2017
