A nitrogen isotopic shift in fish otolith-bound organic matter during the Late Cretaceous.

The nitrogen isotopes of the organic matter preserved in fossil fish otoliths (ear stones) are a promising tool for reconstructing past environmental changes. We analyzed the 15N/14N ratio (δ15N) of fossil otolith-bound organic matter in Late Cretaceous fish otoliths (of Eutawichthys maastrichtiensis, Eutawichthys zideki and Pterothrissus sp.) from three deposits along the US east coast, with two of Campanian (83.6 to 77.9 Ma) and one Maastrichtian (72.1 to 66 Ma) age. δ15N and N content were insensitive to cleaning protocol and the preservation state of otolith morphological features, and N content differences among taxa were consistent across deposits, pointing to a fossil-native origin for the organic matter. All three species showed an increase in otolith-bound organic matter δ15N of ~4‰ from Campanian to Maastrichtian. As to its cause, the similar change in distinct genera argues against changing trophic level, and modern field data argue against the different locations of the sedimentary deposits. Rather, the lower δ15N in the Campanian is best interpreted as an environmental signal at the regional scale or greater, and it may be a consequence of the warmer global climate. A similar decrease has been observed in foraminifera-bound δ15N during warm periods of the Cenozoic, reflecting decreased water column denitrification and thus contraction of the ocean's oxygen deficient zones (ODZs) under warm conditions. The same δ15N-climate correlation in Cretaceous otoliths raises the prospect of an ODZ-to-climate relationship that has been consistent over the last ~80 My, applying before and after the end-Cretaceous mass extinction and spanning changes in continental configuration.

Discovery of novel 4-arylamino-quinazoline derivatives as EGFRL858R/T790M inhibitors with the potential to inhibit the non-small cell lung cancers.

Three series of quinazoline derivatives (7a-j, 8a-o, 9a-l) were designed and synthesized as EGFRL858R/T790M inhibitors. Series 7a-j and 8a-o are urea and thiourea derivatives while category 9a-l contain the Michael receptor active warhead. Most of the compounds exhibited excellent anti-proliferative activity in vitro against several cancer cell lines, including non-small cell lung cancer (NSCLC) cell lines A549 and H1975, among which 14 compounds had strong antiproliferative activity against A549 and H1975 cancer cells. What's more, they also showed moderate to excellent kinase inhibitory activity against EGFRWT and EGFRL858R/T790M. 8o exhibited the best kinase inhibitory activity with IC50 values of 0.8, 2.7 nM against EGFRWT and EGFRL858R/T790M, respectively. Moreover, AO single staining and Annexin V-FITC/PI staining results also indicated that both 8o and 9b significantly induced apoptosis in A549 cells. 8o arrested the cell cycle at S phase and 9b arrested the cell cycle at G1 phase.

Mercury Concentrations and Se:Hg Molar Ratios in Flyingfish (Exocoetus volitans) and Squid (Uroteuthis chinensis).

We measured total mercury (Hg) and selenium (Se) concentrations as well as stable nitrogen (N) isotopic composition in flyingfish and squid muscle tissues from the eastern Indian Ocean and western South China Sea. The results showed that the mean Hg concentration in squid muscle from the western South China Sea was lower than that in the eastern Indian Ocean. The Hg concentrations in flyingfish and squid muscle samples were positively correlated with organism size (length and weight) and δ15N in all the study areas. Furthermore, we found a negative correlation between Se and Hg in molar content of flyingfish and squid muscle from the western South China Sea. The Se:Hg molar ratio was significantly negative correlated with fish weight and δ15N, suggesting that the Se:Hg molar ratio decreases with the increase of fish size and trophic level in the food web.

An updated patent review of small-molecule c-Met kinase inhibitors (2018-present).

INTRODUCTION: c-Met tyrosine kinase receptor is a high-affinity ligand of hepatocyte growth factor (HGF). c-Met is widely expressed in a variety of normal human tissues, but shows abnormally high expression, amplification or mutation in tumour tissues such as lung, gastric and breast cancers. Therefore, the use of c-Met as a target can achieve the inhibition of a series of abnormal physiological processes such as tumourigenesis, development and metastasis. A number of small molecule tyrosine kinase inhibitors targeting c-Met have been successfully marketed. AREAS COVERED: This article reviews recent advances in patented c-Met small molecule inhibitors and their inhibitory activity against various cancer cells from 2018 to date. EXPERT OPINION: To date, small molecule inhibitors targeting c-Met have demonstrated impressive therapeutic efficacy in the clinical setting. Most recent patents have focused on addressing the direction of c-Met amplification and overexpression. Despite the great success in the development of selective c-Met inhibitors, the effects of bypass secretion and mutagenesis have led to a need for new c-Met small molecule inhibitors that are safe, efficient, selective and less toxic with novel structures and effective against other targets.

Cenozoic megatooth sharks occupied extremely high trophic positions.

Trophic position is a fundamental characteristic of animals, yet it is unknown in many extinct species. In this study, we ground-truth the 15N/14N ratio of enameloid-bound organic matter (δ15NEB) as a trophic level proxy by comparison to dentin collagen δ15N and apply this method to the fossil record to reconstruct the trophic level of the megatooth sharks (genus Otodus). These sharks evolved in the Cenozoic, culminating in Otodus megalodon, a shark with a maximum body size of more than 15 m, which went extinct 3.5 million years ago. Very high δ15NEB values (22.9 ± 4.4‰) of O. megalodon from the Miocene and Pliocene show that it occupied a higher trophic level than is known for any marine species, extinct or extant. δ15NEB also indicates a dietary shift in sharks of the megatooth lineage as they evolved toward the gigantic O. megalodon, with the highest trophic level apparently reached earlier than peak size.

Is fish bone subfossil a good archive of heavy metal pollution on Nandao Island, South China Sea?

To examine whether historical fish bones can record the magnitude of heavy metal pollution, we analyzed up to 700 years old fish bone remains extracted from an ornithogenic sediment profile on Nandao Island, South China Sea. Bulk sediments and subfossil fish bones were analyzed for elemental and mineralogical composition, as well as stable carbon and nitrogen isotopes. The results showed that pre-1850 CE fish bones experienced significant diagenesis, and could not be used to reconstruct historical record of heavy metal pollution. Fish bone diagenesis was mainly attributed to the erosion from guano in sediment profile. In contrast, the fish bones from in post-1850 CE time were well preserved and could provide useful information on historical pollution loads over the past 160 years. Since 1850 CE, relatively high concentrations of heavy metals from anthropogenic sources, especially Zn, were recorded in fish bone subfossils on Nandao Island, South China Sea.