Hoven's carp Leptobarbus hoevenii strategized metabolism needs to cope with changing environment.

Current water warming and freshwater acidification undoubtedly affect the life of aquatic animals especially ammonotelic teleost by altering their physiological responses. The effect of temperature (28 °C vs 32 °C) and pH (7 vs. 5) on the metabolic compromising strategies of Hoven's carp (Leptobarbus hoevenii) was investigated in this study. Fishes were conditioned to (i) 28 °C + pH 7 (N28°C); (ii) 32 °C + pH 7 (N32°C); (iii) 28 °C + pH 5 (L28°C) and (iv) 32 °C + pH 5 (L32°C) for 20 days followed by osmorespiration assay. Results showed that feeding performance of Hoven's carp was significantly depressed when exposed to low pH conditions (L28°C and L32°C). However, by exposed Hoven's carp to L32°C induced high metabolic oxygen intake and ammonia excretion to about 2x-folds higher compared to the control group. As for energy mobilization, Hoven's carp mobilized liver and muscle protein under L28°C condition. Whereas under high temperature in both pH, Hoven's carp had the tendency to reserve energy in both of liver and muscle. The findings of this study revealed that Hoven's carp is sensitive to lower water pH and high temperature, thereby they remodeled their physiological needs to cope with the environmental changes condition.

Female tilapia, Oreochromis sp. mobilised energy differently for growth and reproduction according to living environment.

This study was conducted to investigate the energy mobilisation preference and ionoregulation pattern of female tilapia, Oreochromis sp. living in different environments. Three different treatments of tilapia as physiology compromising model were compared; tilapia cultured in recirculating aquaculture system (RAS as Treatment I-RAS), tilapia cultured in open water cage (Treatment II-Cage) and tilapia transferred from cage and cultured in RAS (Treatment III-Compensation). Results revealed that tilapia from Treatment I and III mobilised lipid to support gonadogenesis, whilst Treatment II tilapia mobilised glycogen as primary energy for daily exercise activity and reserved protein for growth. The gills and kidney Na+/K+ ATPase (NKA) activities remained relatively stable to maintain homeostasis with a stable Na+ and K+ levels. As a remark, this study revealed that tilapia strategized their energy mobilisation preference in accessing glycogen as an easy energy to support exercise metabolism and protein somatogenesis in cage culture condition, while tilapia cultured in RAS mobilised lipid for gonadagenesis purposes.

The Discovery of Exarafenib (KIN-2787): Overcoming the Challenges of Pan-RAF Kinase Inhibition.

RAF, a core signaling component of the MAPK kinase cascade, is often mutated in various cancers, including melanoma, lung, and colorectal cancers. The approved inhibitors were focused on targeting the BRAFV600E mutation that results in constitutive activation of kinase signaling through the monomeric protein (Class I). However, these inhibitors also paradoxically activate kinase signaling of RAF dimers, resulting in increased MAPK signaling in normal tissues. Recently, significant attention has turned to targeting RAF alterations that activate dimeric signaling (class II and III BRAF and NRAS). However, the discovery of a potent and selective inhibitor with biopharmaceutical properties suitable to sustain robust target inhibition in the clinical setting has proven challenging. Herein, we report the discovery of exarafenib (15), a highly potent and selective inhibitor that intercepts the RAF protein in the dimer compatible αC-helix-IN conformation and demonstrates anti-tumor efficacy in preclinical models with BRAF class I, II, and III and NRAS alterations.