Discovery of 1H-pyrazolo[3,4-b]pyrazine derivatives as selective allosteric inhibitor of protein tyrosine phosphatase SHP2 for the treatment of KRASG12C-mutant non-small cell lung cancer.

The high expression or mutation of SHP2 can induce cancer, so targeting SHP2 has become a new strategy for cancer treatment. In this study, we used the previously reported SHP2 allosteric inhibitor IACS-13909 as a lead drug for structural derivation and modification, and synthesized three SHP2 inhibitors. Among them, 1H-pyrazolo[3,4-b]pyrazine derivative 4b was a highly selective SHP2 allosteric inhibitor, with an IC50 value of 3.2 nM, and its inhibitory activity was 17.75 times than that of the positive control IACS-13909. The cell proliferation experiment detected that compound 4b would markedly inhibit the proliferation of various cancer cells. Interestingly, compound 4b was highly sensitive to KRASG12C-mutant non-small cell lung cancer NCI-H358 cells, with an IC50 value of 0.58 µM and its antiproliferative activity was 4.79 times than that of IACS-13909. Furthermore, the combination therapy of compound 4b and KRASG12C inhibitor sotorasib would play a strong synergistic effect against NCI-H358 cells. The western blot experiment detected that compound 4b markedly downregulated the phosphorylation levels of ERK and AKT in NCI-H358 cells. Molecular docking study predicted that compound 4b bound to the allosteric site of SHP2 and formed H-bond interactions with key residues Thr108, Glu110, Arg111, and Phe113. In summary, this study aims to provide new ideas for the development of SHP2 allosteric inhibitors for the treatment of KRASG12C mutant non-small cell lung cancer.Communicated by Ramaswamy H. Sarma.

Fucoidan Ameliorates Ferroptosis in Ischemia-reperfusion-induced Liver Injury through Nrf2/HO-1/GPX4 Activation.

Background and Aims: Liver ischemia-reperfusion (IR) injury is a common pathological process in liver surgery. Ferroptosis, which is closely related to lipid peroxidation, has recently been confirmed to be involved in the pathogenesis of IR injury. However, the development of drugs that regulate ferroptosis has been slow, and a complete understanding of the mechanisms underlying ferroptosis has not yet been achieved. Fucoidan (Fu) is a sulfated polysaccharide that has attracted research interest due to its advantages of easy access and wide biological activity. Methods: In this study, we established models of IR injury using erastin as an activator of ferroptosis, with the ferroptosis inhibitor ferrostatin-1 (Fer-1) as the control. We clarified the molecular mechanism of fucoidan in IR-induced ferroptosis by determining lipid peroxidation levels, mitochondrial morphology, and key pathways in theta were involved. Results: Ferroptosis was closely related to IR-induced hepatocyte injury. The use of fucoidan or Fer-1 inhibited ferroptosis by eliminating reactive oxygen species and inhibiting lipid peroxidation and iron accumulation, while those effects were reversed after treatment with erastin. Iron accumulation, mitochondrial membrane rupture, and active oxygen generation related to ferroptosis also inhibited the entry of nuclear factor erythroid 2-related factor 2 (Nrf2) into the nucleus and reduced downstream heme oxygenase-1 (HO-1) and glutathione peroxidase 4 (GPX4) protein levels. However, fucoidan pretreatment produced adaptive changes that reduced irreversible cell damage induced by IR or erastin. Conclusions: Fucoidan inhibited ferroptosis in liver IR injury via the Nrf2/HO-1/GPX4 axis.

[Developing biomass estimation models of young trees in typical plantation on the Qinghai-Tibet Plateau, China.] / é’è—é«˜åŽŸå ¸åž‹äººå·¥æž—å¹¼æ ‘ç”Ÿç‰©é‡æ¨¡åž‹æž„å»º.

Calculation of forest biomass is the basis for global carbon stock estimation, which has been included in national forest inventory projects. The volume-derived biomass method is generally used for trees with diameter at breast height (DBH) larger than 5 cm in most forest carbon sink measurement, which omits young trees (diameter at breast height <6 cm, height >0.3 m) and thus may underestimate ecosystem carbon sink capacity. Based on the biomass data of 137 young trees in five typical plantations on the Tibetan Plateau, independent biomass models were developed using the weighted generalized least squares method, with basic diameter as the predictor instead of DBH. Additive biomass models of controlling directly by proportion functions and controlling by the sum of equations were selected. Additive biomass models for the whole plant and each component were developed by applying weighted nonlinear seemingly uncorrelated regression. The results showed that the binary additive biomass model (R2 reached 0.90-0.99) performed better than the monadic biomass models and independent biomass models for the estimation of total biomass. For different tree species, two forms of the additive models had their own advantages, with neglectable difference in accuracy. From the perspective of forestry production, models of controlling directly by proportion functions were more practical. From the perspective of predictors extraction by remote sensing technology, suitable young tree biomass models were developed for remote sensing estimation. In this study, the additive model had high overall fitting accuracy and could accurately estimate the whole plant and component biomass of young trees in similar climatic environments.

Concise synthesis and applications of enantiopure spirobiphenoxasilin-diol and its related chiral ligands.

The development of chiral architectures for chiral ligand and catalyst discovery is essential for asymmetric catalysis. Herein, we report the concise synthesis of a Si-centered spirocyclic skeleton, spirobiphenoxasilin-diol (SPOSiOL), and its derived chiral ligands. Using the chemical resolution method, the optical SPOSiOL could be obtained in high yield on a gram scale. Preliminary studies indicated that this ligand scaffold has great potential in transition metal-catalyzed asymmetric reactions. This finding further highlights that the Si-centered spirocyclic scaffolds are of great value in asymmetric catalysis.

[Biomechanical affect of percutaneous transforaminal endoscopic discectomy on adjacent segments with different degrees of degeneration:a finite element analysis].

OBJECTIVE: To investigate the biomechanical affect of percutaneous transforaminal endoscopic discectomy(PTED) on adjacent segments with different degrees of degeneration and related risk of adjacent segment diseases (ASD) caused by this operation. METHODS: A healthy male adult volunteer was selected, and the lumbosacral vertebra image data was obtained by CT scan, and the external contour of the bone structure was reconstructed. On this basis, the external contour of the bone structure was fitted by using the smooth curve in 3D-CAD software, and the complete three-dimensional finite element modelof the non degenerate L3-S1 segment and the degenerative models of the L3-L4 and L5-S1 segment were drawn forward. In L4, L5 segment simulating PTED surgery through the removal of right part of articular process and nucleus pulposus and anulus fibrosus. After PTED was simulated in the L4-L5 segment and the risk of ASD has been evaluated by six changes of biomechanical indicators in flexion, extension, left and right lateral bending, left and right axial rotation conditions. RESULTS: In the finite element model without adjacent segmental disc degeneration, the annulus fibrosus von Mises stress and intradiscal pressure of the PTED model showed only a slight increase under most stress conditions, and a slight decrease in a few conditions, and there was no significant change trend before and after surgery. In the original degenerated adjacent segment disc model, the biomechanical indicators related to disc degeneration in the pre- and post-PTED model showed significant deterioration, leading to an increased risk of potential adjacent spondylopathy. CONCLUSION: PTED surgery will not lead to the significant deterioration of postoperative biomechanical environment of non-degeneration adjacent intervertebral discs, and the original degeneration of adjacent intervertebral discs is a important risk factor for ASD.

[Spatial variation of soil carbon and stable isotopes in the southern margin desert of Junggar Basin, China]. / å‡†å™¶å°”ç›†åœ°å—ç¼˜è’æ¼ åŒºåœŸå£¤ç¢³åˆ†å¸ƒåŠå ¶ç¨³å®šåŒä½ç´ å˜åŒ–.

The southern margin desert of Junggar Basin in the central arid region of Asia was selec-ted as the study area. To gain insight into the distribution characteristic of stable carbon isotope and the relationship between the change of soil carbon and the distance to oasis of soil organic carbon (SOC) and soil inorganic carbon (SIC), three belt transects were set according to the distance between the desert and the oasis in edge, middle and hinterland of the desert respectively, and collected the soil profile samples with depth of 2 m. The results indicated that the SOC content reduced with the soil depth, and the variation with the distance to oasis was the edge> the middle> the hinterland. The δ13C value of SOC varied in the range of -21.92‰ to -17.41‰, and decreased with the depth; the range in the middle and hinterland was -25.20‰ to -19.30‰, and increased then declined with the depth. Therefore, we could infer that the C3 plants played a dominant role in the central of desert, and had experienced the succession from C3 plants to C4 plants. The average content of SIC was 38.98 g·kg-1 in the edge of desert, which was about 6.01 folds as large as the content in the hinterland. This indicated that a large number of SIC with 0-2 m depth were clustered in the edge of the desert. The δ13C value of SIC increased first then decreased with the soil depth, and enriched in the bottom layer, which was mainly affected by the original carbonate content and soil carbon dioxide.

An Approach to Optically Pure Bridging Chiral p-tert-Butylcalix[4]arenes through a Homologous Anionic Ortho-Fries Rearrangement.

A novel efficient approach to optically pure bridging chiral calix[4]arenes through a homologous anionic ortho-Fries rearrangement of inherently chiral calix[4]arenes was presented for the first time. As a result, two pairs of N,N'-dimethylformamidyl-substituted bridging chiral p-tert-butylcalix[4]arene enantiomers were facilely obtained. Their absolute configurations were determined through ROESY analysis, ECD comparison, and X-ray crystallographic analysis.

[Dynamics of ecosystem services value in Aksu River watershed in 1960 -2008].

By using GIS-RS techniques and the table 'Equivalent weight of China terrestrial ecosystems services value', in combining with the local grain yield and grain purchasing price, this paper analyzed the changes of ecosystem services value in Aksu River watershed in 1960-2008, and explored the responses of ecosystem services value change in arid trans-boundary river watershed to land use/cover change. Overall, the ecosystem services value in Aksu River watershed in 1960-2008 changed slightly, with the total value increased after an initial decrease. The main cause of the initial decrease was the area decrease of wetland, woodland, and grassland. The area increase of cropland and water body partly offset the loss of the total value, but the loss was still larger than the gain. The contribution of each ecosystem service value to the total ecosystem services value had less change, and the service value from soil formation and protection together with waste treatment contributed most. There was a significant spatial heterogeneity in the magnitude and the variation of ecosystem services value, with the downstream of the watershed changed significantly. Sensitivity analysis indicated that the estimated total ecosystem services value in the study area was inelastic to the services value coefficients, and the results shown in this paper were robust.

[Dynamic change of soil organic matter under different cropping systems in the oasis of Tianshan Mountain northern slope].

Taking the oasis of lower Sangong River watershed in the Tianshan Mountain northern slope as study area, six kinds of cropping systems, including those of saline-alkaline tolerance crop, food crop, melon and vegetables, economic plants-cotton, economic plants-grape, and economic plants-hop, were selected based on the investigation of local cropping systems, and the dynamic change of soil organic matter under effects of these cropping systems was analyzed by using the laboratory data in 1982, 1999 and 2003. The results showed that land policy and market price had a direct effect on the transformation from annuals cropping system to perennials cropping system, while soil organic matter (OM) content experienced a decline in 1982-1999 owing to the transformation from planting other crops to planting cotton, and a rise in 1999-2003 resulting from the conversion from planting food crops and cotton to planting perennial crops. On the whole, the soils in the oasis presented as a carbon sink, suggesting that the change of artificial vegetation in the oasis was helpful to the accumulation of soil OM, and beneficial to the sustainable use of farmland.