Rainstorm and strong wind weathers largely increase greenhouse gases flux in shallow ponds.

Shallow-water ponds represent the hotspots of greenhouse gas (GHG) emissions. Most current studies focus on the temporal dynamics for GHGs in water, with little consideration given to the effects of weather changes. In this study, we measured and compared the concentrations and fluxes of CO2, CH4, and N2O from a pond in Northeast China under different meteorological conditions. Results showed that the rates of CO2, CH4, and N2O emissions from pond into the atmosphere during strong winds were 85.85 ± 7.55 mmol m-2 d-1, 22.05 ± 6.80 mmol m-2 d-1, and 10.87 ± 0.72 µmol m-2 d-1, respectively, significantly higher than those measured during non-rain weather. Among which, over 88 % of CH4 emissions were contributed by ebullition. Meanwhile, the CO2 and N2O flux were also significantly higher during heavy rainfall, reaching 100.05 ± 19.76 mmol m-2 d-1 and 5.90 ± 1.03 µmol m-2 d-1, respectively. Strong winds and precipitation induced sediment disturbances, high gas transport coefficients, reduced photosynthesis and oxygen greatly promoted the GHGs escape evasion. Wind speed, air pressure, solar radiation, and dissolved oxygen in water were important influencing factors. Our results emphasize the importance of capturing short-term weather disturbance events, especially rainstorm and strong winds, to accurately assess the annual GHG budget from these shallow water ecosystems.

A designed cyclic peptide based on Trastuzumab used to construct peptide-drug conjugates for its HER2-targeting ability.

Human epidermal growth factor receptor 2 (HER2) has been recognized as an important therapeutic target for its overexpression in many cancers. Trastuzumab is a monoclonal antibody targeting HER2, which has been approved by FDA to treat HER2-positive cancer. In this research, cyclic peptide Cyclo-GCGPep1 was designed based on the binding mode between antibody and HER2 protein in silico, which has been confirmed possessing good affinity with HER2. Cyclo-GCGPep1 was also used to construct peptide-drug conjugates with Camptothecin. Biological evaluations demonstrated that Conjugate 1 has a good antiproliferative activity on SK-BR-3 and NCI-N87 cells. Conjugate 1 retained the pro-apoptotic and Topo I inhibitory ability of Camptothecin. Meanwhile, it has good targeting ability towards HER2-positive cells with the help of Cyclo-GCGPep1. It also has better permeability in the tumor spheroid model than Camptothecin. In summary, the design of cyclic peptide derived from antibody is of significance for the discovery of targeting peptides and Conjugate 1 is expected as a good therapeutic agent for HER2-positive cancers.

Discovery of a novel GLP-1/GIP dual receptor agonist CY-5 as long-acting hypoglycemic, anti-obesity agent.

Glucagon-like peptide-1 (GLP-1) receptor agonists as an effective approach for type 2 diabetes mellitus (T2DM) has been explored extensively, multi agonists based on GLP-1 may have better clinical benefits on obesity, Nonalcoholic steatohepatitis (NASH) and other metabolic diseases. To get multi agonists based on GLP-1, 15 conjugates were designed, synthesized, and tested for biological activity. GLP-1/glucagon dual receptor agonist E1 showed moderate long-acting hypoglycemic effect, CY-5 and CY-16 with GLP-1/GIP dual receptor agonistic activity exhibited longer duration of continuous blood glucose stabilization. The long-acting hypoglycemic effect was equal to that of semaglutide. Although they have lost the agonistic activity on glucagon receptor, chronic in vivo studies on T2DM mice and diet-induced obesity (DIO) mice showed that CY-5 can effectively reduce food intake, inhibit body weight gain, repair islets damage and improve the glucose tolerance. One month treatment on NASH mice showed that CY-5 can significantly lower the TG, TC, AST, ALT and LDL-C and increase the HDL-C. CY-5 can also improve the liver vacuolation, reduce fat accumulation and delay the process of the fibrosis. The liver protection effect is better than that of semaglutide. In summary, CY-5 is a promising candidate for the treatment of metabolic diseases and worthy for further development.

GLP-1R agonists for the treatment of obesity: a patent review (2015-present).

INTRODUCTION: Glucagon-like peptide-1 (GLP-1) is an endogenous peptide which is secreted by enteroendocrine L cells, GLP-1 receptor agonists (GLP-1 RAs) can exhibit glucoregulation by stimulating insulin release, promote satiety, delay gastric emptying, and reduce energy intake. Liraglutide is the only GLP-1 RA approved for the treatment of obesity. The phase III clinical study of semaglutide has completed and the result showed significant weight loss effect. GLP-1 RAs have been proven to be safe and effective in clinical trials, they are considered to be promising anti-obesity drugs. AREAS COVERED: This review provides an overview of recently published patents describing modified GLP-1 RAs, multi-agonists in the treatment or prevention of obesity from January 2015 to April 2020. Moreover, small molecule GLP-1 RAs, recombinant fusion proteins, combination of GLP-1 RAs with other drugs and the preparation of GLP-1 RAs are also covered. EXPERT OPINION: Currently, research on anti-obesity effect of modified GLP-1 RAs has grown significantly, liraglutide accounts for approximately 56% of the global obesity drug market. Long-acting analogues and multifunctional peptides showed good weight loss activity. As more and more clinical trials are carried out, we believe that GLP-1 RAs will occupy an important position in the market of obesity treatment.

Design, synthesis and biological evaluation of novel 6-phenyl-1,3a,4,10b-tetrahydro-2H-benzo[c]thiazolo[4,5-e]azepin-2-one derivatives as potential BRD4 inhibitors.

Bromodomain-containing protein 4 (BRD4) is a key epigenetic regulator in cancer, and inhibitors targeting BRD4 exhibit great anticancer activity. By replacing the methyltriazole ring of the BRD4 inhibitor I-BET-762 with an N-methylthiazolidone heterocyclic ring, fifteen novel BRD4 inhibitors were designed and synthesized. Compound 13f had a hydrophobic acetylcyclopentanyl side chain, showing the most potent BRD4 inhibitory activity in the BRD4-BD1 inhibition assay (IC50 value of 110 nM), it also significantly suppressed the proliferation of MV-4-11 cells with high BRD4 level (IC50 value of 0.42 µM). Furthermore, the potent apoptosis-promoting and G0/G1 cycle-arresting activity of compound 13f were indicated by flow cytometry. As the downstream-protein of BRD4, c-Myc was in significantly low expression by compound 13f treatment in a dose-dependent manner. All the findings supported that this novel compound 13f provided a perspective for developing effective BRD4 inhibitors.

Discovery of novel potent GPR40 agonists containing imidazo[1,2-a]pyridine core as antidiabetic agents.

Free fatty acid receptor 1 (FFA1 or GPR40) has been studied for many years as a target for the treatment of type 2 diabetes mellitus. In order to increase potency and reduce hepatotoxicity, a series of novel compounds containing imidazo[1,2-a]pyridine scaffold as GPR40 agonist were synthesized. Compound I-14 was identified as an effective agonist as shown by the conspicuous drop in blood glucose in normal and diabetic mice. It had no risk of hepatotoxicity compared with TAK-875. Moreover, good pharmacokinetic (PK) properties of I-14 were observed (CL = 27.26 ml/h/kg, t1/2 = 5.93 h). The results indicate that I-14 could serve as a possible candidate to treat diabetes.

[Stoichiometry of carbon, nitrogen and phosphorus and their allometric relationship between leaves and fine roots of three functional tree seedlings.] / 3ç§åŠŸèƒ½åž‹æž—æœ¨å¹¼è‹—å¶ç‰‡ä¸Žç»†æ ¹ç¢³æ°®ç£·åŒ–å­¦è®¡é‡ç‰¹å¾åŠå ¶å¼‚é€Ÿå ³ç³».

We analyzed the contents and stoichiometric ratios of carbon (C), nitrogen (N) and phosphorus (P) in leaves and fine roots of Machilus pauhoi (an evergreen broad-leaved species), Cerasus campanulata (a deciduous broad-leaved species) and Fokienia hodginsii (an evergreen coniferous species) to compare the leaf and root stoichiometry and allometric relationship between different functional groups of trees. There were significant difference in the contents and stoichiometry of C, N and P in the leaves and fine roots among different functional groups. C content, C/N and C/P of the leaves and roots were the highest in M. pauhoi. N content and N/P of the leaves and roots were the highest in C. campanulata, whereas P content of the leaves and roots was the highest in F. hodginsii. The allometric relationship of C, N and P contents as well as their stoichiometric ratios between the leaves and fine roots showed significant difference, which was affected by functional difference. The allometric relationship between C/P and N/P with significantly different allometric indexes in leaves in seedlings of those three tree species, while the isometric relationship between the contents of N and P was found in fine roots. There were significant difference in the C, N and P stoichiometry between the leaves and fine roots. The allometric relationship between leaf C content and root P content in M. pauhoi was detected. C and N contents and C/N, N/P in leaves generally had the allometric or isokinetic relationships with C/N, N/P of fine roots. There were allometric relationships between the leaf C content and the root C, N and P contents in F. hodginsii. It was concluded that nutrient allocation between leaves and fine roots of C. campanulata was more strongly coordinated. The investment strategy of P for leaves and fine roots across those three tree species was similar. The results provided scientific reference for accurate nutrient management at seedling stage and efficient cultivation technique.