An isoflavone derivative potently inhibits the angiogenesis and progression of triple-negative breast cancer by targeting the MTA2/SerRS/VEGFA pathway

Objective:Angiogenesis plays a vital role in tumor growth and metastasis.Here,we aimed to find novel efficient antiangiogenic molecules targeting vascular endothelial growth factor A(VEGFA)at the transcriptional level to treat triple-negative breast cancer(TNBC).Methods:We used a cell-based seryl tRNA synthetase(SerRS)promoter-driven dual-luciferase reporter system to screen an in-house library of 384 naturally occurring small molecules and their derivatives to find candidate molecules that could upregulate the expression of SerRS,a potent transcriptional repressor of VEGFA.The levels of SerRS and VEGFA were examined by quantitative RT-PCR(qRT-PCR),western blotting,and/or ELISAs in TNBC cells after candidate molecule administration.Zebrafish,the Matrigel plug angiogenesis assay in mice,the TNBC allograft,and xenograft mouse models were used to evaluate thein vivoanti-angiogenic and anti-cancer activities.Furthermore,the potential direct targets of the candidates were identified by proteomics and biochemical studies.Results:We found the most active compound was 3-(4-methoxyphenyl)quinolin-4(1H)-one(MEQ),an isoflavone derivative.In TNBC cells,MEQ treatment resulted in increased SerRS mRNA(P<0.001)and protein levels and downregulated VEGFA production.Both the vascular development of zebrafish and Matrigel plug angiogenesis in mice were inhibited by MEQ.MEQ also suppressed the angiogenesis in TNBC allografts and xenografts in mice,resulting in inhibited tumor growth and prolonged overall survival(P<0.05).Finally,we found that MEQ regulated SerRS transcription by interacting with MTA2(Metastasis Associated 1 Family Member 2).Conclusions:Our findings suggested that the MTA2/SerRS/VEGFA axis is a drug-treatable anti-angiogenic target,and MEQ is a promising anti-tumor molecule that merits further investigation for clinical applications.

生物质糠醛水相加氢重排的研究进展

糠醛是生物质化工中非常重要的呋喃类平台化合物之一,可以被转化为众多精细化学品和燃料添加剂,但在转化过程中易产生寡聚物,影响反应效率。针对糠醛水相加氢重排制备环戊醇反应过程的特点,以金属/酸协调催化体系为切入点,对糠醛水相加氢重排催化剂进行了综述,并在此基础上提出了生物质呋喃类化合物绿色合成环戊醇类产物中存在的问题以及今后的研究方向。

Identification of serum immunoglobulin M(IgM)of crucian carp(Carassius auratus gibelio)and immune response to cyprinid herpesvirus 2 infection

Crucian carp(Carassius auratus gibelio),an extensively cultivated freshwater fish,was one of the model species for the study of fish immunology.Polyclonal antibodies were advantageous molecular tools for studying teleost immune system.Specifically,polyclonal antibodies reacting with immunoglobulins(Ig)were used successfully in studies of the teleost fishes.In the present study,we produced polyclonal antibody against CH2 domains of crucian carp IgM,and measured the in vivo dynamics of IgM mRNA caused by CyHV-2 infection.The recombinant protein IgM with relative molecular weight about 53 KD was correctly expressed in prokaryotic cells.The specificity of the polyclonal antibody was evaluated by Western blotting and results revealed that the antibody not only specifically recognized crucian carp serum but also cross-reacted with grass carp serum.Quantitative RT-PCR analysis demonstrated the expression of IgM mRNA changed significantly after CyHV-2 infection.The expression of IgM in the kidney increased and reached a maximum at 6 h post-infection(hpi),while dropped to a low level at 5 days post-infection(dpi).In conclusion,the expression of IgM was significantly upregulated in the kidney of crucian carp infected with CyHV-2,indicating that IgM played a potential role in systemic immunity against viral infection.Polyclonal antibody against crucian carp IgM had certain clinical relevance,which might provide insight into the early stage of virus infection and prevention of the disease.

相转化纳滤膜的膜材料结构设计及调控策略

非溶剂致相分离技术由于其制膜工艺简便且对膜结构调控手段多样化,在制备高通量、具有选择性筛分特性的纳滤膜上具有显著优势。然而如何进一步提升相转化纳滤膜的分离精度及渗透系数,仍受国内外学者广泛关注。本文首先系统阐述了相转化过程中,铸膜液热力学性质及成膜动力学对膜结构及性能的影响机理。其次总结了传统膜材料,如聚砜、聚醚砜等材料在纳滤膜制备中的研究进展。然后重点分析了两亲性嵌段共聚物材料的特点及在相转化纳滤膜制备中的突出优势。最后,本文展望未来制备高性能相转化纳滤膜的发展方向。

Integrative analysis of DNA methylation and gene expression identified cervical cancer-specific diagnostic biomarkers

Cervical cancer is the leading cause of death among women with cancer worldwide.Here,we performed an integrative analysis of Illumina HumanMethylation450K and RNA-seq data from TCGA to identify cervical cancer-specific DNA methylation markers.We first identified differentially methylated and expressed genes and examined the correlation between DNA methylation and gene expression.The DNA methylation profiles of 12 types of cancers,including cervical cancer,were used to generate a candidate set,and machine-learning techniques were adopted to define the final cervical cancer-specific markers in the candidate set.Then,we assessed the protein levels of marker genes by immunohistochemistry by using tissue arrays containing 93 human cervical squamous cell carcinoma samples and cancer-adjacent normal tissues.Promoter methylation was negatively correlated with the local regulation of gene expression.In the distant regulation of gene expression,the methylation of hypermethylated genes was more likely to be negatively correlated with gene expression,while the methylation of hypomethylated genes was more likely to be positively correlated with gene expression.Moreover,we identified four cervical cancer-specific methylation markers,cg07211381(RAB3C),cg12205729(GABRA2),cg20708961(ZNF257),and cg26490054(SLC5A8),with 96.2%sensitivity and 95.2%specificity by using the tenfold cross-validation of TCGA data.The four markers could distinguish tumors from normal tissues with a 94.2,100,100,and 100%AUC in four independent validation sets from the GEO database.Overall,our study demonstrates the potential use of methylation markers in cervical cancer diagnosis and may boost the development of new epigenetic therapies.

Glucose-sensitive acetylation of Seryl tRNA synthetase regulates lipid synthesis in breast cancer

Abnormally enhanced de novo lipid biosynthesis has been increasingly realized to play crucial roles in the initiation and progression of varieties of cancers including breast cancer.However,the mechanisms underlying the dysregulation of lipid biosynthesis in breast cancer remain largely unknown.Here,we reported that seryl tRNA synthetase(SerRS),a key enzyme for protein biosynthesis,could translocate into the nucleus in a glucose-dependent manner to suppress key genes involved in the de novo lipid biosynthesis.In normal mammary gland epithelial cells glucose can promote the nuclear translocation of SerRS by increasing the acetylation of SerRS at lysine 323.In SerRS knock-in mice bearing acetylation-defective lysine to arginine mutation.

Seryl tRNA synthetase cooperates with POT1 to regulate telomere length and cellular senescence

Deregulated telomere length is a causative factor in many physiological and pathological processes,including aging and cancer.Many studies focusing on telomeres have revealed important roles for cooperation between the Shelterin protein complex and telomerase in maintaining telomere length.However,it remains largely unknown whether and how aging-related stresses,such as deregulated protein homeostasis,impact telomere length.Here,we explored the possible roles of aminoacyl tRNA synthetases(AARSs),key enzymes catalyzing the first reactions in protein synthesis,in regulating telomere length and aging.We selected seryl tRNA synthetase(SerRS)since our previous studies discovered expanded functions of SerRS in the nucleus in addition to its canonical cytoplasmic role in protein synthesis.In this study,we revealed that overexpression of SerRS promoted cellular senescence and inhibited the growth of cervical tumor xenografts in mice by triggering the senescence of tumor cells.In the nucleus,SerRS directly bound to telomeric DNA repeats and tethered more POT1 proteins to telomeres through a direct interaction between the UNE-S domain of SerRS and the OB1 domain of POT1.We further demonstrated that SerRS-induced enrichment of POT1 prevented the recruitment of telomerase to telomeres,resulting in progressive telomere shortening.Our data suggested a possible molecular link between protein synthesis and telomere length control,the deregulation of which may be associated with aging and cancer.

Optical identification of interlayer coupling of graphene/MoS_(2) van der Waals heterostructures

The interlayer coupling in van der Waals(vdW)heterostructures(vdWHs)is at the frontier of the fundamental research,underlying many optical behaviors.The graphene/MoS_(2) vdWHs provide an ideal platform to reveal the good interfacial coupling between graphene and MoS_(2) constituents.Here,three groups of graphene/MoS_(2) vdWHs were prepared by transferring 1–3 layers of graphene onto monolayer MoS_(2).The interlayer coupling within graphene/MoS_(2) vdWHs were characterized and analyzed by Raman spectroscopy,photoluminescence(PL)spectroscopy and optical contrast(OC)spectroscopy.The upshift of the A_(1g) peak of MoS_(2) and the upshift of the D and 2D peaks of SLG show that the electrons move from MoS_(2) to graphene accompanied by the dielectric shielding effect on graphene.The weakened PL intensities and the slight red shift of A peak prove that the electrons move from MoS_(2) to graphene meanwhile the recombination of hole and electron pairs is blocked in vdWHs.Our results deepen the understanding of the interlayer coupling of graphene/MoS_(2) vdWHs and therefore provide guidelines for the practical design and application of optoelectronic devices based on graphene/MoS_(2) vdWHs.

Surface protection method for the magnetic core using covalent organic framework shells and its application in As(Ⅲ)depth removal from acid wastewater

Fe_(3)O_(4)-based materials are widely used for magnetic separation from wastewater.However,they often suffer from Fe-leaching behavior under acidic conditions,decreasing their ac-tivity and limiting sustainable practical applications.In this study,covalent organic frame-works(COFs)were used as the shell to protect the Fe_(3)O_(4) core,and the Fe_(3)O_(4)@COF core-shell composites were synthesized for As(Ⅲ)removal from acid wastewater.The imine-linked COFs can in situ grow on the surface of the Fe_(3)O_(4) core layer by layer with[COFs/Fe_(3)O_(4)]mol ratio of up to 2∶1.The Fe-leaching behavior was weakened over a wide pH range of 1-13.Moreover,such composites keep their magnetic characteristic,making them favorable for nanomaterial separation.As(Ⅲ)batch adsorption experiments results indicated that,when COFs are used as the shell for the Fe_(3)O_(4) core,a balance between As(Ⅲ)removal efficiencies and the thickness of the COF shell exists.Higher As(Ⅲ)removal efficiencies are obtained when the[COFs/Fe_(3)O_(4)]mol ratios were<1.5∶1,but thicker COF shells were not beneficial for As(Ⅲ)removal.Such composites also exhibited better As(Ⅲ)removal performances in the pH range of 1-7.Over a wide pH range,the zeta potential of Fe_(3)O_(4)@COF core-shell compos-ites becomes more positive,which benefits the capture of negative arsenic ions.In addition,thinner surface COFs were favorable for mass transfer and facilitating the reaction of Fe and As elements.Our study highlights the promise of using COFs in nanomaterial surface protection and achieving As(Ⅲ)depth removal under acidic conditions.

E6-induced selective translation of WNT4 and JIP2 promotes the progression of cervical cancer via a noncanonical WNT signaling pathway

mRNA translation reprogramming occurs frequently in many pathologies,including cancer and viral infection.It remains largely unknown whether viral-induced alterations in mRNA translation contribute to carcinogenesis.Most cervical cancer is caused by high-risk human papillomavirus infection,resulting in the malignant transformation of normal epithelial cells mainly via viral E6 and E7 oncoproteins.Here,we utilized polysome profiling and deep RNA sequencing to systematically evaluate E6-regulated mRNA translation in HPV18-infected cervical cancer cells.We found that silencing E6 can cause over a two-fold change in the translation efficiency of~653 mRNAs,most likely in an eIF4E-and eIF2α-independent manner.In addition,we identified that E6 can selectively upregulate the translation of WNT4,JIP1,and JIP2,resulting in the activation of the noncanonical WNT/PCP/JNK pathway to promote cell proliferation in vitro and tumor growth in vivo.Ectopic expression of WNT4/JIP2 can effectively rescue the decreased cell proliferation caused by E6 silencing,strongly suggesting that the WNT4/JIP2 pathway mediates the role of E6 in promoting cell proliferation.Thus,our results revealed a novel oncogenic mechanism of E6 via regulating the translation of mRNAs.

Characterization of grass carp FosB, Fosl2, JunD transcription factors in response to GCRV infection

Activating protein-1(AP-1)composed of Jun and Fos family proteins,which are frequently activated by pathogens to induce cellular inflammation and immune responses.In this study,by using RNA sequencing(RNA-seq)technology,we found that FosB,Fosl2,and JunD expression was co-induced 12 and 20 h in grass carp(Ctenopharyngodon idella)kidney cell line(CIK cells)after grass carp reovirus(GCRV)infection.Full-length cDNA of the three genes were cloned and phylogenetic analysis indicated that the corresponding proteins shared high homology with those in higher vertebrates.The tissue distribution analysis of the three genes showed they were ubiquitously expressed in various tissues of healthy grass carp.In infection assay,FosB,Fosl2,and JunD were up-regulated and co-expressed 8 h after GCRV infection in CIK cells.Protein interaction and co-expression network analysis revealed that FosB,Fosl2,and JunD showed similar functions and were co-expressed in mammals and fish.Taken together,these results indicated that the co-expression of the AP-1 family proteins in grass carp uniformly responds to GCRV infection.These findings provided insights into the further study of AP-1 transcription factors function during grass carp reovirus infection.

Use of Different Murder Weapons by a Single Murderer:Two Case Reports

Homicide is an extremely serious crime,and although the offender usually uses the same weapon to initially injure and complete the killing,there are exceptions.We report two cases in which a single murderer killed a victim using different weapons and summarize several situations in which a murderer might use different weapons to kill.The number of murders should be determined and estimated after a comprehensive complicated investigation of the scene,careful examination of the victim’s injuries,and evaluation of evidence reported by eyewitnesses.

Suicide Deaths in China:An Analysis of Forensic Cases

Suicide cases are often encountered during death investigations in forensic medicine.In this study,through a comparative analysis of our own data of 98 suicide cases and previous reports from various forensic institutions in China,we analyzed the risk factors of Chinese suicides and explored the implications thereof from a forensic point of view.Moreover,the age and sex differences,means,causes,and other concerns regarding suicide are discussed along with a review of the literature.