Identification of novel immune ferroptosis-specific genes associated with prognostic features in hepatocellular carcinoma

Background:As the most common iron metabolism and storage organ,the specific regulatory mechanism and prognostic relevance of hepatocellular carcinoma(HCc)need further study.Objective:We aimed to perform a multi-omics integration and a ferroptosis-associated signature of HCC.Methods:Gene Expression Omnibus was searched for available data with ferroptosis inducers,and three independent datasets(GSE104462,GSE112384,and GSE142591)were collected.Multi-omic data with available clinical information of TCGA-LIHC and CHCC were retrieved from the Cancer Genome Atlas(TCGA,http://cancergenome.nih.gov/)and iProX database(www.iprox.org,IPx0000937000).Integrated multi-omics analyses revealed the difference among biological functions,the activation status of key signaling pathways,tumor microenvironment,and sorafenib resistance in HCC.Single-sample gene set enrichment analysis(ssGSEA)identified a novel panel associated with clinical and molecular attributes,including survival,immune microenvironment,sorafenib resistance,genetic profile,liver-specific proteome,and phosphoproteome.Results:We performed a multi-omics integrationfor ferroptosis-associated characterization of HCC using paired tumor and adjacent liver tissues from 370 samples of TCGA.We proposed a novel panel including twelve genes that could reflect the prognosis and capacity of ferroptosis(ATAD2,DTL,DUT,E2F2,GINS2,FOXK1,MCM4,MCM5,MTHFD1,PHF19,POLA1,THOC6).Samples with high ferroptosis prognostic scores suggested significantly inferior survival(P=0.0028),a lower degree of ferroptosis(P<0.001),and greater ferroptosis induction capacity(P<0.001).Conclusion:The score in our study revealed the inherent state and further potential of ferroptosis in tumor cells,which also distinct features in tumor metabolism,microenvironment,clinical phenotype,and potential therapeutics.

Large yellow croaker(Larimichthys crocea)mitofusin 2 inhibits type I IFN responses by degrading MAVS via enhanced K48‑linked ubiquitination

In mammals,mitofusin 2(MFN2)is involved in mitochondrial fusion,and suppresses the virus-induced RIG-I-like receptor(RLR)signaling pathway.However,little is known about the function of MFN2 in non-mammalian species.In the present study,we cloned an MFN2 ortholog(LcMFN2)in large yellow croaker(Larimichthys crocea).Phylogenetic analysis showed that MFN2 emerged after the divergence of amphioxus and vertebrates.The protein sequences of MFN2 were well conserved from fsh to mammals.LcMFN2 was expressed in all the tissues/organs examined at diferent levels,and its expression was upregulated in response to poly(I:C)stimulation.Overexpression of LcMFN2 inhibited MAVS-induced type I interferon(IFN)promoter activation and antiviral gene expression.In contrast,knockdown of endogenous LcMFN2 enhanced poly(I:C)induced production of type I IFNs.Additionally,LcMFN2 enhanced K48-linked polyubiquitination of MAVS,promoting its degradation.Also,overexpression of LcMFN2 impaired the cellular antiviral response,as evidenced by the increased expression of viral genes and more severe cytopathic efects(CPE)in cells infected with spring viremia of carp virus(SVCV).These results indicated that LcMFN2 inhibited type I IFN response by degrading MAVS,suggesting its negative regulatory role in cellular antiviral response.Therefore,our study sheds a new light on the regulatory mechanisms of the cellular antiviral response in teleosts.

Systematic analysis of clinical relevance and molecular characterization of m^(6)A in COVID-19 patients

N6-methyladenosine(m6A)is the most prevalent post-transcriptional RNA modification in mRNA and long non-coding RNAs of eukaryotes,and its biological functions are mediated by m6A writers,erasers and readers.1 A nuclear methyltransferase complex consisting of METTL3,METTL14,WTAP,VIRMA,ZC3H13,RBM15(or RBM15B),YWHAG,TRA2A and CAPRIN1 catalyzes the m6A modifications,acting as m6A writers.1 m6A demethylase ALKBH5 as well as m6A demethylase FTO mediate the demethylation of m6As,acting as the m6A erasers.

Effectiveness of azithromycin mass drug administration on trachoma:a systematic review

Backgrounds:Azithromycin mass drug administration(MDA)is a key part of the strategy for controlling trachoma.This systematic review aimed to comprehensively summarize the present studies of azithromycin MDA on trachoma;provide an overview of the impact of azithromycin MDA on trachoma in different districts;and explore the possible methods to enhance the effectiveness of azithromycin MDA in hyperendemic districts.Methods:PubMed,Embase,the Cochrane Central Register of Controlled Trials,Web of Science,and ClinicalTrials.gov were searched up to February 2021 with no language restriction.Studies reporting the effect of azithromycin MDA on trachoma were included.Mathematical modeling studies,animal studies,case reports,and reviews were excluded.The trachomatous inflammation-follicular(TF)<5.0%was used to judge the effect of azithromycin MDA on eliminating trachoma as a public health problem.Two researchers independently conducted the selection process and risk of bias assessment.Results:A total of 1543 studies were screened,of which 67 studies including 13 cluster-randomized controlled trials and 54 non-randomized studies were included.The effect of azithromycin MDA on trachoma was closely related to the baseline prevalence in districts.For the districts with baseline prevalence between 5.0%and 9.9%,a single round of MDA achieved a TF<5.0%.For the districts with baseline between 10.0%and 29.9%,annual MDA for 3 to 5 years reduced TF<5.0%.However,for the districts with high level of baseline prevalence(TF>30.0%),especially with baseline TF>50.0%,annual MDA was unable to achieve the TF<5.0%even after 5 to 7 years of treatment.Quarterly MDA is more effective in controlling trachoma in these hyperendemic districts.Conclusions:Azithromycin MDA for controlling trachoma depends on the baseline prevalence.The recommendation by the World Health Organization that annual MDA for 3 to 5 years in the districts with TF baseline>10.0%is not appropriate for all eligible districts.