Discovery and Optimization of Potent and Orally Available CTP Synthetase Inhibitors for Use in Treatment of Diseases Driven by Aberrant Immune Cell Proliferation.

Herein, we report the discovery of a first-in-class chemotype 2-(alkylsulfonamido)thiazol-4-yl)acetamides that act as pan-selective inhibitors of cytidine 5'-triphosphate synthetase (CTPS1/2), critical enzymes in the de novo pyrimidine synthesis pathway. Weak inhibitors identified from a high-throughput screening of 240K compounds have been optimized to a potent, orally active agent, compound 27, which has shown significant pharmacological responses at 10 mg/kg dose BID in a well-established animal model of inflammation.

The salt glands of Tamarix usneoides E. Mey. ex Bunge (South African Salt Cedar).

Tamarix usneoides is a halophyte tree endemic to south-western Africa. This species is known to excrete a range of ions from specialized glandular structures on its leaves. To understand the mechanisms involved in the transport, sequestration and excretion of ions by the glands, a study was performed on salt gland distribution and ultrastructure. The glands are vesiculated trichomes, comprised of eight cells viz. two basal collecting cells and six excretory cells, partially bounded by a secondary cell wall that could serve as an impermeable barrier, forcing excess ions to move from the apoplast of the surrounding tissue into the cytoplasm of the basal excretory cells. It was hypothesized that the ions are moved across the excretory cells in endocytotic vesicles that fuse with the plasmalemma or form junctional complexes, allowing ion movement from one excretory cell to the next. In the apical cell, the vesicles fuse with the plasmalemma, releasing the ions into the network of cell wall ingrowths which channel the ions to the outside surface of the cell. This study shows that there are distinct structural adaptations for the processing of ions for excretion, although the mechanism by which ions enter the cells still needs to be determined.

Cold pretreatment amplifies the responses of in vitro Eucalyptus grandis shoots to cryopreparative drying.

BACKGROUND: Eucalyptus grandis is an important commercial forestry species in South Africa. Little is known about its response (which is both drought and cold sensitive) to cold exposure and subsequent drying. OBJECTIVE: The study was to investigate the responses of E. grandis in vitro shoots to cold pretreatment. METHODS: E. grandis in vitro shoots were subjected to cold pretreatment (5, 10 and 15 degrees C at different exposure periods of 1 or 3 days), different drying times (20, 40, 60 and 80 min over activated silica gel), and the combination of the selected cold pretreatment regime and subsequent drying. RESULTS: Cold pretreatment alone did not cause detrimental effects but elicited the accumulation of phenolic acids. Shoots exposed to 5 degrees C for 3 days had significantly higher levels of reactive oxygen species as well. The accumulation of ROS and phenolic acids was also noted in unacclimated, dried shoots, especially after 80 min of drying. In addition, these shoots had significantly higher levels of total soluble sugars, lower levels of starch and elevated proline levels. CONCLUSION: This osmotic adjustment strategy was amplified in cold acclimated, dried shoots (10 degrees C, 3 days; 80 min drying), which also had significantly lower levels of ROS, increased levels of phenolic acid, and higher water content and viability.