River capture in the middle reaches of the palaeo-Yarlung Zangbo River.

There are 51 tributaries in the middle reaches of the Yarlung Zangbo River (YZR), and the confluences of 87% of the tributaries west of Jiacha Gorge are high-angle or perpendicular, reflecting the anomalous development of these tributaries. In this paper, field investigation and digital elevation model (DEM) methods were used to analyse the causes of this anomalous phenomenon, and it was found that there was a watershed in the area of the Jiacha Gorge. The palaeo-YZR west of the Jiacha Gorge flowed westward before the early Pleistocene into the Zada, Zhongba, Jilong and Gamba-Dingri palaeolakes, which featured a large amount of total accommodation space in the western Qinghai-Tibet Plateau; thus, this river was a continental river. With the intensification of the collision between the Indian plate and the Eurasian plate, the Qinghai-Tibet Plateau experienced rapid uplift and formed a landscape with high elevations in the west and lower elevations in the east, promoting the headward erosion of the eastward-flowing river. During the early Pleistocene, the river east of the Jiacha Gorge crossed the watershed and captured the palaeo-YZR, causing a reversal in the flow direction of the palaeo-YZR.

Design, Synthesis, and Evaluation of a Series of Novel Super Long-Acting DPP-4 Inhibitors for the Treatment of Type 2 Diabetes.

In the present work, a novel series of trifluoromethyl-substituted tetrahydropyran derivatives were rationally designed and synthesized as potent DPP-4 inhibitors with significantly improved duration time of action over current commercially available DPP-4 inhibitors. The incorporation of the trifluoromethyl group on the 6-position of the tetrahydropyran ring of omarigliptin with the configuration of (2R,3S,5R,6S) not only significantly improves the overall pharmacokinetic profiles in mice but also maintains comparable DPP-4 inhibition activities. Further preclinical development of compound 2 exhibited its extraordinary efficacy in vivo and good safety profile. Clinical studies of compound 2 (Haisco HSK7653) are now ongoing in China, which revealed that inhibitor 2 could serve as an efficient candidate with a once-biweekly therapeutic regimen.

Design, Synthesis, and Evaluation of a Series of Novel Benzocyclobutene Derivatives as General Anesthetics.

In the present work, a series of structurally novel benzocyclobutene derivatives were identified as general anesthetics through the loss of righting reflex (LORR) experiment on mice. Our initial efforts found compound 1a with a fused four-membered ring on the 2,3-position of the phenol ring could significantly improve the safety profile. Further SAR study revealed that small hydrogen bond acceptor (HBA) groups are optimal for good ED50 along with much broader therapeutic windows, such as compounds 16b and 17. Present work demonstrates the superiority of this novel benzocyclobutene scaffold.