Estimation of the Mixed Layer Depth in the Indian Ocean from Surface Parameters: A Clustering-Neural Network Method.

The effective estimation of mixed-layer depth (MLD) plays a significant role in the study of ocean dynamics and global climate change. However, the methods of estimating MLD still have limitations due to the sparse resolution of the observed data. In this study, a hybrid estimation method that combines the K-means clustering algorithm and an artificial neural network (ANN) model was developed using sea-surface parameter data in the Indian Ocean as a case study. The oceanic datasets from January 2012 to December 2019 were obtained via satellite observations, Argo in situ data, and reanalysis data. These datasets were unified to the same spatial and temporal resolution (1° × 1°, monthly). Based on the processed datasets, the K-means classifier was applied to divide the Indian Ocean into four regions with different characteristics. For ANN training and testing in each region, the gridded data of 84 months were used for training, and 12-month data were used for testing. The ANN results show that the optimized NN architecture comprises five input variables, one output variable, and four hidden layers, each of which has 40 neurons. Compared with the multiple linear regression model (MLR) with a root-mean-square error (RMSE) of 5.2248 m and the HYbrid-Coordinate Ocean Model (HYCOM) with an RMSE of 4.8422 m, the RMSE of the model proposed in this study was reduced by 27% and 22%, respectively. Three typical regions with high variability in their MLDs were selected to further evaluate the performance of the ANN model. Our results showed that the model could reveal the seasonal variation trend in each of the selected regions, but the estimation accuracy showed room for improvement. Furthermore, a correlation analysis between the MLD and input variables showed that the surface temperature and salinity were the main influencing factors of the model. The results of this study suggest that the pre-clustering ANN method proposed could be used to estimate and analyze the MLD in the Indian Ocean. Moreover, this method can be further expanded to estimate other internal parameters for typical ocean regions and to provide effective technical support for ocean researchers when studying the variability of these parameters.

Discovery of (2-phenylthiazol-4-yl)urea derivatives that induce neuronal differentiation from mesenchymal stem cells.

The success of stem cells therapy to treat neurodegenerative diseases is currently restricted by the lack of suitable stem cells. Mesenchymal stem cells (MSCs) have demonstrated several advantages as seed-cells for the stem cells therapy. In particular, the low immunogenicity and multiple lineages differentiation capability enables the possibility of using MSCs to treat neurodegenerative diseases. However, a more potent neuronal differentiation capacity of MSCs is required during a success treatment against neurodegenerative diseases. Bioengineering using small molecules to boost the neuronal differentiation of MSCs has been proposed as a promising strategy. Herein, we developed a new series of (2-phenylthiazol-4-yl)urea derivatives and one of them, 18g were observed to successfully promote neuronal differentiation of MSCs after culturing MSCs with 18g for 4 days. In addition, neither significant cytotoxicity nor cell cycle altering were found after the incubation. Interestingly, the osteogenic differentiation potential of MSCs was not affected after 18g treatment. The present study provides a promising small molecule to boost the innate neuronal differentiation capacity of MSCs with no serious detrimental effects.

Discovery of Novel Indazoles as Potent and Selective PI3Kδ Inhibitors with High Efficacy for Treatment of Hepatocellular Carcinoma.

PI3Kδ inhibitors have been developed for treatment of B-cell malignancies and inflammatory and autoimmune diseases. However, their therapeutic role in solid tumors like hepatocellular carcinoma (HCC) is rarely reported. Thus, the development of potent and selective PI3Kδ inhibitors with a new chemotype and therapy is highly desirable. Through the scaffold-hopping strategy, indazole was first described as the core structure of propeller-shaped PI3Kδ inhibitors. A total of 26 indazole derivatives were designed and prepared to identify a novel compound 9x with good isoform selectivity, PK profile, and potency. Compared to Idelalisib and Sorafenib, the pharmacodynamic (PD) studies showed that 9x exhibits superior efficacy in HCC cell lines and xenograft models, and the mechanistic study showed that 9x robustly suppresses the downstream AKT pathway to induce subsequent apoptotic cell death in HCC models. Therefore, this work provides a new structural design of PI3Kδ inhibitors for a novel and efficient therapeutic small molecule toward HCC.

Lysosomal Reacidification Ameliorates Vinyl Carbamate-Induced Toxicity and Disruption on Lysosomal pH.

Ethyl carbamate (EC) is a carcinogen toxicant, commonly found in fermented foods and beverages. The carcinogenic and toxic possibility of EC is thought to be related to its metabolite vinyl carbamate (VC). However, we found interesting mechanisms underlying VC-induced toxicity in this study, which were greatly different from EC. We first conducted a simple synthesis procedure for VC and found that VC possessed higher toxicity but failed to regulate levels of reactive oxygen species, glutathione, and autophagy. Notably, VC treatment resulted in upregulation of lysosomal pH, which was responsible for its cytotoxicity. Cyclic adenosine monophosphate (cAMP) pretreatment could enhance restoration of lysosomal acidity and ameliorate VC-induced damage. Inhibition of protein kinase A and cystic fibrosis transmembrane conductance regulator can block cAMP-induced cytoprotection. Together, our results provided the evidence for novel mechanisms of toxicity and possible protection method under VC exposure, which might give new perspectives on the study of EC-induced toxicity.

One possible mechanism for eddy distribution in zonal current with meridional shear.

Oceanic mesoscale eddies are common, especially in areas where zonal currents with meridional shear exists. The nonlinear effects complicate the analysis of mesoscale eddy dynamics. This study proposes a solitary (eddy) solution based on an asymptotic expansion of the nonlinear potential vorticity equation with a constant meridional shear of zonal current. This solution reveals several important consequences. For example, cyclonic (anticyclonic) eddies can be generated by the negative (positive) shear of the zonal current. Furthermore, the meridional structure of an eddy is asymmetrical, and the center of a cyclonic (anticyclonic) eddy tilts poleward (equatorward). Eddy width is inversely proportional to shear intensity. Eddy phase speed is proportional to shear intensity and the wave amplitude, and their spatial distribution show band-like pattern as they propagate westward. This nonlinear solitary solution is an extension of classical linear Rossby theory. Moreover, these findings could be applied to other areas with similar zonal current shear.

Metal-free α-alkylation of alcohols with para-quinone methides.

A metal-free α-alkylation of alcohols with para-quinone methides (p-QMs) for accessing alcohol-containing phenols and dihydroisocoumarins has been developed. The alcohols were converted to α-oxy radicals in the presence of di-tert-butyl peroxide (DTBP), which were added to p-QMs for aromatization and C(sp3)-C(sp3) bond formation.

Fe(III)-Catalyzed Hydroallylation of Unactivated Alkenes with Morita-Baylis-Hillman Adducts.

An Fe(III)-catalyzed hydroallylation of unactivated alkenes with Morita-Baylis-Hillman adducts via an Fe-catalyzed process is described. A variety of alkenes, including mono-, di-, and trisubstituted alkenes, could all smoothly convert to structural diversified cinnamates in this protocol. Interestingly, when the hydroxyl-containing alkenes were used, various lactones could be rapidly assembled. Moreover, this protocol could be applied to late-stage functionalization of natural products.

Rh(iii)-catalyzed C-H activation/cyclization of oximes with alkenes for regioselective synthesis of isoquinolines.

A Rh(iii)-catalyzed C-H activation/cyclization of oximes and alkenes for facile and regioselective access to isoquinolines has been developed. This protocol features mild reaction conditions and easily accessible starting materials, and has been applied to the concise synthesis of moxaverine. A kinetic isotope effect study was conducted and a plausible mechanism was proposed.

Fe-Catalyzed Hydroalkylation of Olefins with para-Quinone Methides.

A novel Fe-catalyzed hydroalkylation of olefins with para-quinone methides (p-QMs) for accessing phenols has been developed. In this protocol, various olefins could convert to alkyl radicals and undergo addition to para-quinone methides toward C-C bond formation and aromatization. The reaction conditions are mild and the substrate scopes are broad.

Fe-Catalyzed Olefin Hydroamination with Diazo Compounds for Hydrazone Synthesis.

A novel Fe-catalyzed olefin hydroamination with diazo compounds for accessing hydrazones has been developed. Diazo compounds are used as radical acceptors and can be trapped by the in situ generated alkyl radical toward C-N bond formation. The reaction conditions are mild, and the substrate scope is broad. Additionally, this hydroamination protocol is applicable for intramolecular reactions to construct diverse heterocycles.