Discovery of potent and selective c-Met inhibitors for MET-amplified hepatocellular carcinoma treatment.

Hepatocellular carcinoma (HCC) is a prevalent and lethal malignancy worldwide. The MET gene, which encodes receptor tyrosine kinase c-Met, is aberrantly activated in various solid tumors, including non-small cell lung cancer and HCC. In this study, we identified a novel c-Met inhibitor 54 by virtual screening and structural optimization. Compound 54 showed potent c-Met inhibition with an IC50 value of 0.45 ± 0.06 nM. It also exhibited high selectivity among 370 kinases and potent anti-proliferative activity against MET-amplified HCC cells. Moreover, compound 54 displayed significant anti-tumor efficacy in vivo, making it a potential candidate for HCC treatment in future studies.

Cotton 4-coumarate-CoA ligase 3 enhanced plant resistance to Verticillium dahliae by promoting jasmonic acid signaling-mediated vascular lignification and metabolic flux.

Lignins and their antimicrobial-related polymers cooperatively enhance plant resistance to pathogens. Several isoforms of 4-coumarate-coenzyme A ligases (4CLs) have been identified as indispensable enzymes involved in lignin and flavonoid biosynthetic pathways. However, their roles in plant-pathogen interaction are still poorly understood. This study uncovers the role of Gh4CL3 in cotton resistance to the vascular pathogen Verticillium dahliae. The cotton 4CL3-CRISPR/Cas9 mutant (CR4cl) exhibited high susceptibility to V. dahliae. This susceptibility was most probably due to the reduction in the total lignin content and the biosynthesis of several phenolic metabolites, e.g., rutin, catechin, scopoletin glucoside, and chlorogenic acid, along with jasmonic acid (JA) attenuation. These changes were coupled with a significant reduction in 4CL activity toward p-coumaric acid substrate, and it is likely that recombinant Gh4CL3 could specifically catalyze p-coumaric acid to form p-coumaroyl-coenzyme A. Thus, overexpression of Gh4CL3 (OE4CL) showed increasing 4CL activity that augmented phenolic precursors, cinnamic, p-coumaric, and sinapic acids, channeling into lignin and flavonoid biosyntheses and enhanced resistance to V. dahliae. Besides, Gh4CL3 overexpression activated JA signaling that instantly stimulated lignin deposition and metabolic flux in response to pathogen, which all established an efficient plant defense response system, and inhibited V. dahliae mycelium growth. Our results propose that Gh4CL3 acts as a positive regulator for cotton resistance against V. dahliae by promoting JA signaling-mediated enhanced cell wall rigidity and metabolic flux.

Deep reptilian evolutionary roots of a major avian respiratory adaptation.

Vertebral ribs of the anterior thorax in extant birds bear bony prongs called uncinate processes, which improve the mechanical advantage of mm. appendicocostales to move air through the immobile lung and pneumatic air sacs. Among non-avian archosaurs, broad, cartilaginous uncinate processes are present in extant crocodylians, and likely have a ventilatory function. Preserved ossified or calcified uncinate processes are known in several non-avian dinosaurs. However, whether other fossil archosaurs possessed cartilaginous uncinate processes has been unclear. Here, we establish osteological correlates for uncinate attachment to vertebral ribs in extant archosaurs, with which we inferred the presence of uncinate processes in at least 19 fossil archosaur taxa. An ancestral state reconstruction based on the infer distribution suggests that cartilaginous uncinate processes were plesiomorphically present in Dinosauria and arguably in Archosauria, indicating that uncinate processes, and presumably their ventilatory function, have a deep evolutionary history extending back well beyond the origin of birds.

Discovery of Novel Phosphoinositide-3-Kinase α Inhibitors with High Selectivity, Excellent Bioavailability, and Long-Acting Efficacy for Gastric Cancer.

Phosphoinositide-3-kinase (PI3K) overexpressed in many tumors is a promising target for cancer therapy. However, due to toxicity from the ubiquitous expression of PI3K in many tissues, the development of PI3K inhibitors with high selectivity and low toxicity has become an urgent need for tumor treatment. Herein, based on the HipHop, we designed and synthesized a series of 6-(4,6-dimorpholino-1,3,5-triazin-2-yl)benzo[d]oxazol-2-amine derivatives as potent, selective, and long-acting PI3Kα inhibitors. Compound 27 was determined with potent PI3Kα inhibitory activity (IC50 = 4.4 nM), which exhibited excellent selectivity for homologous PI3K enzymes and a 370 kinome panel. Meanwhile, 27 featured favorable stability (T1/2 > 10 h) and high bioavailability (130%). Importantly, compound 27 exerted great antigastric cancer activity in vivo when combined with taxol. Collectively, these characteristics suggested 27 to be a promising PI3K agent for cancer treatment.

Taphonomy and taxonomy of a juvenile lambeosaurine (Ornithischia: Hadrosauridae) bonebed from the late Campanian Wapiti Formation of northwestern Alberta, Canada.

Hadrosaurid (duck-billed) dinosaur bonebeds are exceedingly prevalent in upper Cretaceous (Campanian-Maastrichtian) strata from the Midwest of North America (especially Alberta, Canada, and Montana, U.S.A) but are less frequently documented from more northern regions. The Wapiti Formation (Campanian-Maastrichtian) of northwestern Alberta is a largely untapped resource of terrestrial palaeontological information missing from southern Alberta due to the deposition of the marine Bearpaw Formation. In 2018, the Boreal Alberta Dinosaur Project rediscovered the Spring Creek Bonebed, which had been lost since 2002, along the northern bank of the Wapiti River, southwest of Grande Prairie. Earlier excavations and observations of the Spring Creek Bonebed suggested that the site yielded young hadrosaurines. Continued work in 2018 and 2019 recovered ~300 specimens that included a minimum of eight individuals, based on the number of right humeri. The morphology of several recovered cranial elements unequivocally supports lambeosaurine affinities, making the Spring Creek sample the first documented occurrence of lambeosaurines in the Wapiti Formation. The overall size range and histology of the bones found at the site indicate that these animals were uniformly late juveniles, suggesting that age segregation was a life history strategy among hadrosaurids. Given the considerable size attained by the Spring Creek lambeosaurines, they were probably segregated from the breeding population during nesting or caring for young, rather than due to different diet and locomotory requirements. Dynamic aspects of life history, such as age segregation, may well have contributed to the highly diverse and cosmopolitan nature of Late Cretaceous hadrosaurids.

Taxonomic revision of Eoalligator (Crocodylia, Brevirostres) and the paleogeographic origins of the Chinese alligatoroids.

Background. The primarily Neotropical distribution of living alligatoroids raises questions as to when and how the ancestors of Alligator sinensis migrated to China. As phylogeny provides a necessary framework for historical biogeographic issues, determining the phylogenetic positions of the Chinese alligatoroids is a crucial step towards understanding global alligatoroid paleobiogeography. Besides the unnamed alligatoroids from the Eocene of Guangdong Province, three Chinese fossil taxa have been referred to Alligatoroidea: Alligator luicus, Eoalligator chunyii and Eoalligator huiningensis. However, none of these fossil taxa has been included in a phylogenetic analysis. The genus Eoalligator was established to accommodate E. chunyii from Guangdong Province. E. huiningensis from Anhui Province was later erected as a second species, despite no distinctive similarities with E. chunyii. By contrast, the putative crocodyline Asiatosuchus nanlingensis was established based on material from Guangdong Province, close to the E. chunyii specimens geographically and stratigraphically. Furthermore, specimens of A. nanlingensis and E. chunyii share four distinctive characters, but display no evident differences. As a result, the taxonomic relationships of these three species require restudy. Methods. In this paper, all specimens of E. chunyii and E. huiningensis are reassessed in detail, and compared to specimens of A. nanlingensis. Detailed re-descriptions and revised diagnoses are provided, and a cladistic analysis is carried out to assess the phylogenetic positions of E. chunyii, E. huiningensis and A. nanlingensis. Results. The analysis recovers E. chunyii and A. nanlingensis as sister taxa among basal Crocodylidae, while P. huiningensis is posited as an alligatoroid. Two key characters support the monophyly E. chunyii + A. nanlingensis: sulcus within surangular, and anteroposteriorly oriented surangular-articular suture. The former character is unique to E. chunyii and A. nanlingensis among crocodyloids, although a smaller and more posteriorly positioned surangular fossa is known in Diplocynodon. Detailed comparisons show the two species to be synonymous, with E. chunyii as the junior synonym of A. nanlingensis based on page priority. Because E. chunyii was erected as the type species of Eoalligator, the genus is now invalid. We establish the new genus Protoalligator to accommodate "Eoalligator" huiningensis, an alligatoroid whose exact phylogenetic position is uncertain. In particular, P. huiningensis retains primitive characters such as a lacrimal that extends further anteriorly than the prefrontal, and a notch at the premaxilla-maxilla suture. However, P. huiningensis also appears to share one important derived character, a complete nasal bar, with alligators. Our taxonomic revisions imply that four alligatoroids are currently known from China, and these species must have dispersed from North America to Asia in more than one event.