Two H3K36 methyltransferases differentially associate with transcriptional activity and enrichment of facultative heterochromatin in rice blast fungus

Di-and tri-methylation of lysine 36 on histone H3(H3K36me2/3)is catalysed by histone methyltransferase Set2,which plays an essential role in transcriptional regulation.Although there is a single H3K36 methyltransferase in yeast and higher eukaryotes,two H3K36 methyltransferases,Ash1 and Set2,were present in many filamentous fungi.However,their roles in H3K36 methylation and transcriptional regulation remained unclear.Combined with methods of RNA-seq and ChIP-seq,we revealed that both Ash1 and Set2 are redundantly required for the full H3K36me2/3 activity in Magnaporthe oryzae,which causes the devastating worldwide rice blast disease.Ash1 and Set2 distinguish genomic H3K36me2/3-marked regions and are differentially associated with repressed and activated transcription,respectively.Furthermore,Ash1-catalysed H3K36me2 was co-localized with H3K27me3 at the chromatin,and Ash1 was required for the enrichment and transcriptional silencing of H3K27me3-occupied genes.With the different roles of Ash1 and Set2,in H3K36me2/3 enrichment and transcriptional regulation on the stress-responsive genes,they differentially respond to various stresses in M.oryzae.Overall,we reveal a novel mechanism by which two H3K36 methyltransferases catalyze H3K36me2/3 that differentially associate with transcriptional activities and contribute to enrichment of facultative heterochromatin in eukaryotes.

Demethylzeylasteral induces PD-L1 ubiquitin-proteasome degradation and promotes antitumor immunity via targeting USP22

Programmed cell death ligand-1(PD-L1)is a T cell inhibitory immune checkpoint molecule that interacts with programmed cell death-1(PD-1)to promote immune escape of tumor cells.Compared with antibody therapies,small molecule drugs show better prospects due to their advantages such as higher bioavailability,better tissue penetration,and reduced risk of immunogenicity.Here,we found that the small molecule demethylzeylasteral(Dem)can significantly downregulate the expression of PD-L1 in colorectal cancer cells and enhance the killing effect of T cells on tumor cells.Mechanistically,Dem binds to the deubiquitinating enzyme USP22 and promotes its degradation,resulting in increased ubiquitination and degradation of PD-L1 through the proteasome pathway.In addition,Dem increased the activity of cytotoxic T cells and reduced the number of myeloid-derived suppressor cells(MDSCs)and regulatory T cells(Tregs)in tumor-infiltrating lymphocytes(TILs),thereby activating the tumor immune microenvironment and inhibiting the growth of subcutaneous MC38 tumors in C57BL/6 mice.Moreover,we also found that the combination of Dem and CTLA4 antibodies can further improve the efficacy of antitumor therapy.Our study reveals the mechanism by which Dem promotes PD-L1 degradation and suggests that the combination of Dem and CTLA4 antibodies may improve the efficacy of immunotherapy.

非水系锂空气电池催化剂

近年来,随着对高性能电池需求的加大,锂空气电池因其超高的理论能量密度成为了研究热点。虽然锂空气电池的发展已取得了一些突破性的进展,但离实际应用差距甚远,仍有很多问题和挑战需要解决。其中,氧电极反应动力学速度缓慢就是一个非常严重的问题。为了促进锂空气电池的发展和应用,国际学术界对改善氧电极动力学速度的催化剂开展了大量的研究工作。本文总结了近年来国内外关于锂空气电池氧电极催化材料的主要研究进展,并对其未来发展作了前景展望。

Histone deacetylase inhibitors inhibit cervical cancer growth through Parkin acetylationmediated mitophagy

Parkin,an E3 ubiquitin ligase,plays a role in maintaining mitochondrial homeostasis through targeting damaged mitochondria for mitophagy.Accumulating evidence suggests that the acetylation modification of the key mitophagy machinery influences mitophagy level,but the underlying mechanism is poorly understood.Here,our study demonstrated that inhibition of histone deacetylase(HDAC)by treatment of HDACis activates mitophagy through mediating Parkin acetylation,leading to inhibition of cervical cancer cell proliferation.Bioinformatics analysis shows that Parkin expression is inversely correlated with HDAC2 expression in human cervical cancer,indicating the low acetylation level of Parkin.Using mass spectrometry,Parkin is identified to interact with two upstream molecules,acetylase acetyl-Co A acetyltransferase 1(ACAT1)and deacetylase HDAC2.Under treatment of suberoylanilide hydroxamic acid(SAHA),Parkin is acetylated at lysine residues 129,220 and 349,located in different domains of Parkin protein.In in vitro experiments,combined mutation of Parkin largely attenuate the interaction of Parkin with PTEN induced putative kinase 1(PINK1)and the function of Parkin in mitophagy induction and tumor suppression.In tumor xenografts,the expression of mutant Parkin impairs the tumor suppressive effect of Parkin and decreases the anticancer activity of SAHA.Our results reveal an acetylation-dependent regulatory mechanism governing Parkin in mitophagy and cervical carcinogenesis,which offers a new mitophagy modulation strategy for cancer therapy.

Predictability and dynamics of the rapid intensification of Super Typhoon Lekima (2019)

This study explores the effect of the initial axisymmetric wind structure and moisture on the predictability of the peak intensity of Typhoon Lekima(2019)through a 20-member ensemble forecast using the WRF model.The ensemble members are separated into Strong and Weak groups according to the maximum 10-m wind speed at 48 h.In our study of Lekima(2019),the initial intensity defined by maximum 10-m wind speed is not a good predictor of the intensity forecast.The peak intensity uncertainty is sensitive to the initial primary circulation outside the radius of maximum wind(RMW)and the initial secondary circulation.With greater absolute angular momentum(AAM)beyond the RMW directly related to stronger primary circulation,and stronger radial inflow,Strong group is found to have larger AAM import in lowlevel,helping to spin up the TC.Initial moisture in innercore is also critical to the intensity predictability through the development of inner-core convection.The aggregation and merger of convection,leading to the TC intensification,is influenced by both radial advection and gradient of system-scale vortex vorticity.Three sensitivity experiments are conducted to study the effect of model uncertainty in terms of model horizontal grid resolution on intensity forecast.The horizontal grid resolution greatly impacts the predictability of Lekima’s intensity,and the finer resolution is helpful to simulate the intensification and capture the observed peak value.

Ensemble data assimilation and prediction of typhoon and associated hazards using TEDAPS:evaluation for 2015-2018 seasons

The initial condition accuracy is a major concern for tropical cyclone(TC)numerical forecast.The ensemble-based data assimilation techniques have shown great promise to initialize TC forecast.In addition to initial condition uncertainty,representing model errors(e.g.physics deficiencies)is another important issue in an ensemble forecasting system.To improve TC prediction from both deterministic and probabilistic standpoints,a Typhoon Ensemble Data Assimilation and Prediction System(TEDAPS)using an ensemble-based data assimilation scheme and a multi-physics approach based on Weather Research and Forecasting(WRF)model,has been developed in Shanghai Typhoon Institute and running realtime since 2015.Performance of TED APS in the prediction of track,intensity and associated disaster has been evaluated for the Western North Pacific TCs in the years of 2015-2018,and compared against the NCEP GEFS.TED APS produces markedly better intensity forecast by effectively reducing the weak biases and therefore the degree of underdispersion compared to GEFS.The errors of TED APS track forecasts are comparative with(slightly worse than)those of GEFS at longer(shorter)forecast leads.TEDAPS ensemble-mean exhibits advantage over deterministic forecast in track forecasts at long lead times,whereas this superiority is limited to typhoon or weaker TCs in intensity forecasts due to systematical underestimation.Four case-studies for three landfalling cyclones and one recurving cyclone demonstrate the capacities of TEDAPS in predicting some challenging TCs,as well as in capturing the forecast uncertainty and the potential threat from TC-associated hazards.