Effects of Organic Selenium on Growth Properties, Selenium Absorption and Utilization, Antioxidant Activity and Immunity in Weaning Piglets

This experiment was conducted to determine the influences of adding organic selenium (Se) on growth properties, Se absorption and utilization, immunity and antioxidant activity in diets of Duroc weaning piglets. This study was performed on 36 (average weight 7.6 kg) weaning piglets. The weaning piglets were randomly allocated to 1 of 4 homogeneous treatments (A, control treatment, no added Se;B, Sodium selenite, 0.3 mg Se/kg feed;C, yeast Se, 0.3 mg Se/kg;D, DL-methionine Se 0.3 mg Se/kg). Every treatment had 3 replicates, every replicate had 3 piglets. The experiment lasted for 35 d, with the first 7 d for adaptation. Feed intake, residual and contaminated feed were recorded every day. Every piglet weight was weighted respectively at beginning and end of experiment. Daily intake, gain weight and feed conversion rates of every replicate were calculated finally. Se concentrations of serum, blood antioxidant and immunity index were analyzed in the 36th d of experiment. The results showed average daily gain of treatment C was significant higher (P 0.05) and D had higher trend than that of treatment A and B (P = 0.06) respectively. And feed and gain ratio of C and D had trends to lower than them of A and B (P = 0.14). However, all the intake of every week and whole period had no significant differences among treatments (P > 0.05). At same time, except for the Immunoglobulin M of treatment D and C was higher than that of treatment A and B significantly (P < 0.05), all the other Se contents of serum, immunity indexes, blood cell parameters and enzymatic activities had no significant differences among treatments (P > 0.05). But they took on some obvious trends. For example, the Se contents and glutathione peroxidase activities increased successively in order of treatment A, B, C and D;the blood urea nitrogen and total bilirubin of treatment A had higher trend than that of other treatments (P = 0.06). All in all, adding to organic Se in basal diets could improve the animal’s healthy levels, growth properties and Se utilization to some extent. Relatively speaking, the DL-methionine Se had more advantages compared to yeast Se.

Ferroptosis:a critical mechanism of N^(6)-methyladenosine modification involved in carcinogenesis and tumor progression

Ferroptosis is an iron-dependent regulatory cell necrosis induced by iron overload and lipid peroxidation.It occurs when multiple redoxactive enzymes are ectopically expressed or show abnormal function.Hence,the precise regulation of ferroptosis-related molecules is mediated across multiple levels,including transcriptional,posttranscriptional,translational,and epigenetic levels.N^(6)-methyladenosine(m^(6)A)is a highly evolutionarily conserved epigenetic modification in mammals.The m^(6)A modification is commonly linked to tumor proliferation,progression,and therapy resistance because it is involved in RNA metabolic processes.Intriguingly,accumulating evidence suggests that dysregulated ferroptosis caused by the m^(6)A modification drives tumor development.In this review,we summarized the roles of m^(6)A regulators in ferroptosis-mediated malignant tumor progression and outlined the m^(6)A regulatory mechanism involved in ferroptosis pathways.We also analyzed the potential value and application strategies of targeting m^(6)A/ferroptosis pathway in the clinical diagnosis and therapy of tumors.

Induction of membraneless organelles as a strategy for HIV-1 post-nuclear entry steps

As intracellular parasites,viruses must modulate the environment of host cells to facilitate viral genome replication and virion assembly.One strategy is to establish specialized,membrane-associated subcellular structures to concentrate viral and cellular components and mediate viral replication processes.This strategy is utilized by many positive-strand RNA viruses such as coronaviruses,hepatitis C virus,and Zika virus,and they re-organize host endo-membranes to form double-membrane vesicles for viral genome replication(Wolff et al.,2020).

Role of tegument proteins in herpesvirus assembly and egress

Morphogenesis and maturation of viral particles is an essential step of viral replication.An infectious herpesviral particle has a multilayered architecture,and contains a large DNA genome,a capsid shell,a tegument and an envelope spiked with glycoproteins.Unique to herpesviruses,tegument is a structure that occupies the space between the nucleocapsid and the envelope and contains many virus encoded proteins called tegument proteins.Historically the tegument has been described as an amorphous structure,but increasing evidence supports the notion that there is an ordered addition of tegument during virion assembly,which is consistent with the important roles of tegument proteins in the assembly and egress of herpesviral particles.In this review we first give an overview of the herpesvirus assembly and egress process.We then discuss the roles of selected tegument proteins in each step of the process,i.e.,primary envelopment,deenvelopment,secondary envelopment and transport of viral particles.We also suggest key issues that should be addressed in the near future.

Remodeling of host membranes during herpesvirus assembly and egress

Many viruses,enveloped or non-enveloped,remodel host membrane structures for their replication,assembly and escape from host cells.Herpesviruses are important human pathogens and cause many diseases.As large enveloped DNA viruses,herpesviruses undergo several complex steps to complete their life cycles and produce infectious progenies.Firstly,herpesvirus assembly initiates in the nucleus,producing nucleocapsids that are too large to cross through the nuclear pores.Nascent nucleocapsids instead bud at the inner nuclear membrane to form primary enveloped virions in the perinuclear space followed by fusion of the primary envelopes with the outer nuclear membrane,to translocate the nucleocapsids into the cytoplasm.Secondly,nucleocapsids obtain a series of tegument proteins in the cytoplasm and bud into vesicles derived from host organelles to acquire viral envelopes.The vesicles are then transported to and fuse with the plasma membrane to release the mature virions to the extracellular space.Therefore,at least two budding and fusion events take place at cellular membrane structures during herpesviruses assembly and egress,which induce membrane deformations.In this review,we describe and discuss how herpesviruses exploit and remodel host membrane structures to assemble and escape from the host cell.

Identification of new type I interferon- stimulated genes and investigation of their involvement in IFN-β activation

Virus infection induces the production of type I interferons （IFNs）. IFNs bind to their heterodimeric receptors to initiate downstream cascade of signaling, leading to the up-regulation of interferon-stimulated genes （ISGs）. ISGs play very important roles in innate immunity through a variety of mechanisms. Although hundreds of ISGs have been identified, it is commonly recognized that more ISGs await to be discovered. The aim of this study was to identify new ISGs and to probe their roles in regulating virus-induced type I IFN production. We used consensus interferon （Con-IFN）, an artificial alpha IFN that was shown to be more potent than naturally existing type I IFN, to treat three human immune cell lines, CEM, U937 and Daudi cells. Microarray analysis was employed to identify those genes whose expres- sions were up-regulated. Six hundred and seventeen genes were up-regulated more than 3-fold. Out of these 617 genes, 138 were not previously reported as ISGs and thus were further pursued. Validation of these 138 genes using quantitative reverse transcription PCR （qRT-PCR） confirmed 91 genes. We screened 89 genes for those involved in Sendal virus （SeV）-induced IFN-13 promoter activation, and PIM1 was identified as one whose expression inhibited SeV-mediated IFN-β activation. We provide evidence indicating that PIM1 specifically inhibits RIG-I- and MDA5-mediated IFN-β signaling. Our results expand the ISG library and iden- tify PIM1 as an ISG that participates in the regulation of virus-induced type I interferon production.

Crystal structure and functional implication of the RUN domain of human NESCA

NESCA,a newly discovered signaling adapter protein in the NGF-pathway,contains a RUN domain at its N-terminus.Here we report the crystal structure of the NESCA RUN domain determined at 2.0-Åresolution.The overall fold of the NESCA RUN domain comprises nine helices,resembling the RUN domain of RPIPx and the RUN1 domain of Rab6IP1.However,compared to the other RUN domains,the RUN domain of NESCA has significantly different surface electrostatic distributions at the putative GTPase-interacting interface.We demonstrate that the RUN domain of NESCA can bind H-Ras,a downstream signaling molecule of TrkA,with high affinity.Moreover,NESCA RUN can directly interact with TrkA.These results provide new insights into how NESCA participates in the NGF-TrkA signaling pathway.

Murine gammaherpesvirus-68 ORF38 encodes a tegument protein and is packaged into virions during secondary envelopment

Tegument is the unique structure of a herpesvirion which occupies the space between nucleocapsid and envelope. Accumulating data have indicated that inter- actions among tegument proteins play a key role in virion morphogenesis. Morphogenesis of gam- maherpesviruses including Kaposi＇s sarcoma-associ- ated herpesvirus （KSHV） and Epstein-Barr virus （EBV） is poorly understood due to the lack of efficient de novo lytic replication in cell culture. Murine gammaherpesvi- rus-68 （MHV-68） is genetically related to these two human herpesviruses and serves as an effective model to study the lytic replication of gammaherpesviruses. We previously showed that ORF33 of MHV-68 encodes a tegument protein and plays an essential role in virion maturation in the cytoplasm. However, the molecular mechanism of how ORF33 participates in virion mor- phogenesis has not been elucidated. In this study we demonstrated that ORF38 of MHV-68 is also a tegument protein and is localized to cytoplasmic compartments during both transient transfection and viral infection. Immuno-gold labeling assay showed that ORF38 is only present on virions that have entered the cytoplasmic vesicles, indicating that ORF38 is packaged into virions during secondary envelopment. We further showed that ORF38 co-localizes with ORF33 during viral infection; therefore, the interaction between ORF38 and ORF33 is conserved among herpesviruses. Notably, we found that although ORF33 by itself is distributed in both the nucleus and the cytoplasm, in the presence of ORF38, ORF33 is co-localized to trans-Golgi network （TGN）, a site where secondary envelopment takes place.

CCAAT/enhancer binding proteins play a role in oriLyt-dependent genome replication during MHV-68 de novo infection

Murine gammaherpesvirus 68(MHV-68),a member of the gammaherpesvirus family,replicates robustly in permissive cell lines and is able to infect laboratory mice.MHV-68 has emerged as a model for studying the basic aspects of viral replication and host–virus interactions of its human counterparts.Herpesvirus genome replication is mediated through a cis-element in the viral genome called the origin of lytic replication(oriLyt).A family of transcription factors,CCAAT/enhancer binding proteins(C/EBPs),assists in oriLyt-mediated DNA replication during gammaherpesvirus reactivation.In this study,we examined the role of C/EBPs in gammaherpesvirus DNA replication during de novo infection,using MHV-68 as a model.We found that C/EBP α and β bind to the CCAAT boxes in the MHV-68 oriLyt core region both in vitro and in vivo,as demonstrated by electrophoretic mobility shift assay and chromatin immunoprecipitation assay.A dominant negative form of C/EBPs significantly impaired the lytic replication efficiency of MHV-68 on both the plasmid and genome levels in a replication assay,indicating that functional C/EBPs are required for maximal MHV-68 genome DNA replication.Collectively,our data demonstrate that C/EBPs interact with the oriLyt core region and play an important role in MHV-68 lytic DNA replication during de novo infection.