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Depression is a serious psychological disorder with a rapidly increasing incidence in recent years. Clinically, selective serotonin reuptake inhibitors are the main therapy. These drugs, have serious adverse reactions, however. Traditional Chinese medicine has the characteristics of multiple components, targets, and pathways, which has huge potential advantages for the treatment of depression. The antidepressant potential of the herbal combination of Bupleurum chinense DC (Chaihu) and Paeonia lactiflora Pall (Baishao) has been extensively studied previously. In this review, we summarized the antidepressant active components and mechanism of Chaihu-Baishao herb pair. We found that it works mainly through relieving oxidative stress, regulating HPA axis, and protecting neurons. Nevertheless, current research of this combined preparation still faces many challenges. On one hand, most of the current studies only stay at the level of animal models, lacking of sufficient clinical double-blind controlled trials for further verification. In addition, studies on the synergistic effect between different targets and signaling pathways are scarce. On the other hand, this preparation has numerous defects such as poor stability, low solubility, and difficulty in crossing the blood-brain barrier.

As a maladaptive disordered eating behavior, binge eating (BE) onset has been reported in children as young as eight years old and is linked with a range of negative psychological consequences. However, previous neuroimaging research of BE has mainly focused on adults in clinical conditions, and little is known about the potential neurostructural and neurofunctional bases of BE in healthy children.In this study, we examined these issues in 76 primary school students (mean age = 9.86 years) using voxel-based morphometry and resting-state functional connectivity (rsFC) approaches.After controlling for age, sex, and total intracranial volume/head motion, we observed that higher levels of BE were correlated with greater gray matter volumes (GMV) in the left fusiform and right insula and weaker rsFC between the right insula and following three regions: right orbital frontal cortex, left cingulate gyrus, and left superior frontal gyrus. No significant associations were observed between BE and regional white matter volume. Significant sex differences were found only in the relationship between BE and GMV in the left fusiform. Furthermore, the GMV- and rsFC-based predictive models (a machine-learning method) achieved significant correlations between the actual and predicted BE values, demonstrating the robustness of our findings.The present study provides novel evidence for the brain structural and functional substrates of children's BE, and further reveals that the weakened communication between core regions associated with negative affectivity, reward responsivity, and executive function is strongly related to dysregulated eating.Level V, descriptive study.

In recent years, Duck Tembusu virus (DTMUV) is becoming an important emerging and re-emerging pathogen that severely harms the poultry industry in China. The DTMUV disease was principally identified by a sharp decline in egg production, whereas few studies were focused on the virus-reproductive system interaction, especially male reproductive system. Herein, the present study was aimed at investigating the in vivo morphological changes in testis from DTMUV-infected adult Shaoxing ducks. After DTMUV infection, the gross observation indicated that the testis of DTMUV-infected ducks was significantly atrophied at 2 days post-infection (dpi), 4 dpi, and 8 dpi. At microscopic and ultrastructural level, morphological analysis revealed that DTMUV could lead to cytoplasmic vacuolation and exfoliation in seminiferous epithelium, decrease in the diameter of seminiferous tubule (ST), and even induce interstitial inflammation in duck testis. Ulteriorly, the spermatogenic cells, especially spermatocytes, are identified as the target cells of DTMUV infection in the testis of ducks through immunohistochemistry (IHC). And more notably, single virus particles and clustered virus particles were observed in the spermatogenic cells from infected ducks. In summary, our results comprehensively illustrated the effects of DTMUV infection on the testis, the morphological changes underlying testicular atrophy and identified the target cells of DTMUV infection in the testis of ducks.

Endometriosis is an inflammatory disease with non-specific symptoms, including chronic pelvic pain and infertility, which affects thousands of women of reproductive age. Early diagnosis of endometriosis remains challenging. We aimed to build a diagnostic model based on m6A methylation-related genes to provide a new perspective on the clinical diagnosis of endometriosis. Two datasets from previous endometriosis studies were selected. GSE51981 was for training and GSE7305 was for validation. The expression of m6A methylation-related genes between proliferative eutopic endometrium from women with and without endometriosis was compared. Most m6A methylation-related genes were down-regulated in eutopic endometrium from women with endometriosis than those without it. The random forest classifier identified 5 significant differentially expressed genes (YTHDF2, NKAP, FTO, ZCCHC4 and HNRNPC) that might be involved in the development of endometriosis by affecting miRNA maturation or immune cell infiltration. These genes were included in a logistic regression to construct a new diagnostic model for endometriosis with an area under the ROC curve of 0.852. The model was tested on another independent dataset（AUC 0.750）and not only diagnosed endometriosis well but also showed how severe it was. We also found that YTHDF2 was very good at diagnosing endometriosis on its own and was correlated with macrophage and neutrophil infiltration that may be important for endometriosis development. In conclusion, this novel diagnostic model using m6A methylation-related genes may be a new method for early non-invasive diagnosis of endometriosis.

The development of endometriosis is closely linked to macrophages, and the type M1 macrophage has been hypothesized to play an inhibitory role in its progression. Escherichia coli induces macrophage polarization toward M1 in numerous diseases and differs in the reproductive tract of patients with and without endometriosis; however, its specific role in endometriosis development remains unknown. Therefore, in this study, E. coli was selected as a stimulator to induce macrophages, and its effects on the growth of endometriosis lesions in vitro and in vivo were investigated using C57BL/6N female mice and endometrial cells. It was revealed that E. coli inhibited the migration and proliferation of co-cultured endometrial cells by IL-1 in vitro and prevented the growth of lesions and induced macrophage polarization toward M1 in vivo. However, this change was counteracted by C–C motif chemokine receptor 2 inhibitors, suggesting that it was associated with bone marrow-derived macrophages. Overall, the presence of E. coli in the abdominal cavity may be a protective factor for endometriosis.

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Detection of EBV-specific IgG in sera from incident NPC cases and healthy controls in the SCHS cohort. Heatmap depicting IgG heavy and light chain-specific (IgGH+L) detection values from 20 incident NPC case-control pairs and the data is represented similarly to Fig 2 with Fisher’s exact test identifying proteins (bolded) that discriminate case from controls and denoted *p

Table S1. Baseline demographic and lifestyle characteristics of study participants who developed nasopharyngeal carcinoma (cases) and those who remained cancer free (controls), the Singapore Chinse Health Study and the Shanghai Cohort Study; Table S2. EBV ORF Expression Library; Table S3. Anti-EBV IgA prediction or protection of NPC by EBV ORF class; Table S4. Anti-EBV IgG prediction or protection of NPC by EBV ORF class; Table S5. Detection of EBNA1 IgA in NPC cases sorted from the shortest to the longest time interval from blood collection to diagnosis of NPC, along with matched controls in the Singapore Chinese Health Study (SCHS) and the Shanghai Cohort Study (SCS).

EBV Expression Library; Multiplex Immunoblot Assay; Conservation Plots

Purpose:The favorable prognosis of stage I and II nasopharyngeal carcinoma (NPC) has motivated a search for biomarkers for the early detection and risk assessment of Epstein-Barr virus (EBV)–associated NPC. Although EBV seropositivity is ubiquitous among adults, a spike in antibodies against select EBV proteins is a harbinger of NPC. A serologic survey would likely reveal which EBV antibodies could discriminate those at risk of developing NPC.Experimental Design:Lysates from a new EBV mammalian expression library were used in a denaturing multiplex immunoblot assay to survey antibodies against EBV in sera collected from healthy individuals who later developed NPC (incident cases) in a prospective cohort from Singapore and validated in an independent cohort from Shanghai, P.R. China.Results:We show that IgA against EBV nuclear antigen 1 (EBNA1) discriminated incident NPC cases from matched controls with 100% sensitivity and 100% specificity up to 4 years before diagnosis in both Singapore and Shanghai cohorts. Incident NPC cases had a greater IgG repertoire against lytic-classified EBV proteins, and the assortment of IgA against EBV proteins detected by the immunoblot assay increased closer to diagnosis.Conclusions:Although NPC tumors consistently harbor latent EBV, the observed heightened systemic and mucosal immunity against lytic-classified antigens years prior to clinical diagnosis is consistent with enhanced lytic transcription. We conclude that an expanding EBV mucosal reservoir (which can be latent and/or lytic) is a risk factor for NPC. This presents an opportunity to identify those at risk of developing NPC using IgA against EBNA1 as a biomarker.

Supplementary Figure from M6A RNA Methylation Regulates Histone Ubiquitination to Support Cancer Growth and Progression

Osteosarcoma is the most common malignancy of the bone, yet the survival for patients with osteosarcoma is virtually unchanged over the past 30 years. This is principally because development of new therapies is hampered by a lack of recurrent mutations that can be targeted in osteosarcoma. Here, we report that epigenetic changes via mRNA methylation holds great promise to better understand the mechanisms of osteosarcoma growth and to develop targeted therapeutics. In patients with osteosarcoma, the RNA demethylase ALKBH5 was amplified and higher expression correlated with copy-number changes. ALKBH5 was critical for promoting osteosarcoma growth and metastasis, yet it was dispensable for normal cell survival. Methyl RNA immunoprecipitation sequencing analysis and functional studies showed that ALKBH5 mediates its protumorigenic function by regulating m6A levels of histone deubiquitinase USP22 and the ubiquitin ligase RNF40. ALKBH5-mediated m6A deficiency in osteosarcoma led to increased expression of USP22 and RNF40 that resulted in inhibition of histone H2A monoubiquitination and induction of key protumorigenic genes, consequently driving unchecked cell-cycle progression, incessant replication, and DNA repair. RNF40, which is historically known to ubiquitinate H2B, inhibited H2A ubiquitination in cancer by interacting with and affecting the stability of DDB1-CUL4–based ubiquitin E3 ligase complex. Taken together, this study directly links increased activity of ALKBH5 with dysregulation of USP22/RNF40 and histone ubiquitination in cancers. More broadly, these results suggest that m6A RNA methylation works in concert with other epigenetic mechanisms to control cancer growth.Significance:RNA demethylase ALKBH5 upregulates USP22 and RNF40 to inhibit histone H2A ubiquitination and induces expression of key replication and DNA repair–associated genes, driving osteosarcoma progression.

Supplementary Data from M6A RNA Methylation Regulates Histone Ubiquitination to Support Cancer Growth and Progression

BG45 is a class Ⅰ histone deacetylase inhibitor (HDACI) with selectivity for HDAC3. Our previous study demonstrated that BG45 can upregulate the expression of synaptic proteins and reduce the loss of neurons in the hippocampus of APPswe/PS1dE9 (APP/PS1) transgenic mice (Tg). The entorhinal cortex is a pivotal region that, along with the hippocampus, plays a critical role in memory in the Alzheimer’s disease (AD) pathology process. In this study, we focused on the inflammatory changes in the entorhinal cortex of APP/PS1 mice and further explored the therapeutic effects of BG45 on the pathologies. The APP/PS1 mice were randomly divided into the transgenic group without BG45 (Tg group) and the BG45-treated groups. The BG45-treated groups were treated with BG45 at 2 months (2 m group), at 6 months (6 m group), or twice at 2 and 6 months (2 and 6 m group). The wild-type mice group (Wt group) served as the control. All mice were killed within 24 h after the last injection at 6 months. The results showed that amyloid-β (Aβ) deposition and IBA1-positive microglia and GFAP-positive astrocytes in the entorhinal cortex of the APP/PS1 mice progressively increased over time from 3 to 8 months of age. When the APP/PS1 mice were treated with BG45, the level of H3K9K14/H3 acetylation was improved and the expression of histonedeacetylase1, histonedeacetylase2, and histonedeacetylase3 was inhibited, especially in the 2 and 6 m group. BG45 alleviated Aβ deposition and reduced the phosphorylation level of tau protein. The number of IBA1-positive microglia and GFAP-positive astrocytes decreased with BG45 treatment, and the effect was more significant in the 2 and 6 m group. Meanwhile, the expression of synaptic proteins synaptophysin, postsynaptic density protein 95, and spinophilin was upregulated and the degeneration of neurons was alleviated. Moreover, BG45 reduced the gene expression of inflammatory cytokines interleukin-1β and tumor necrosis factor-α. Closely related to the CREB/BDNF/NF-kB pathway, the expression of p-CREB/CREB, BDNF, and TrkB was increased in all BG45 administered groups compared with the Tg group. However, the levels of p-NF-kB/NF-kB in the BG45 treatment groups were reduced. Therefore, we deduced that BG45 is a potential drug for AD by alleviating inflammation and regulating the CREB/BDNF/NF-kB pathway, and the early, repeated administration of BG45 can play a more effective role.

Lotus (Nelumbo nucifera) was used as model plant in this study to explore its physiology and molecular response upon short-term exposure to silver nano-particles (AgNPs). Accumulation patterns demonstrated a potential uptake of AgNPs by roots and transport to the leaves as a likely key translocation route in lotus. AgNPs exposure was negatively correlated with lotus growth, including germination rate and petiole length in a concentration-dependent manner. Synthesis of chloroplast pigments in lotus leaves was enhanced by low AgNPs concentration, but were inhibited at high concentration. Hydrogen peroxide (H

Hibernation is a biological status during which hibernating animals acclimatize themselves to reduced energy consumption through extreme but governed decline in self-metabolism. The role of mitochondria (Mt) in metabolic suppression during hibernation has already been elaborated in different organs and species. Nonetheless, the concretely changing process of mitochondrial architecture and the mechanism underlying this transformation during hibernation remains unclear. Herein, the present study was aimed at clarifying the detailed alteration of mitochondrial morphology and its potential role in the Chinese soft-shelled turtle (Pelodiscus sinensis) during different stages of hibernation. Compared with the nonhibernation period, the mitochondrial architecture was changing from round to crescent, and lipid droplet (LD)/Mt interaction was enhanced during hibernation, as observed by transmission electron microscopy (TEM). Further ultrastructural analysis uncovered that mitochondrial fusion was promptly accelerated in the early stage of hibernation, followed by mitochondrial fission in the middle stage, and mitophagy was boosted in the late stage. Moreover, gene and protein expression related to mitochondrial fusion, fission, and mitophagy accorded closely with the mitochondrial ultrastructural changes in different stages of hibernation. Taken together, our results clarified that the transformation of mitochondrial architecture and mitochondrial dynamics are of vital importance in maintaining internal environment homeostasis of Pelodiscus sinensis.

Osteosarcoma is the most common malignancy of the bone, yet the survival for patients with osteosarcoma is virtually unchanged over the past 30 years. This is principally because development of new therapies is hampered by a lack of recurrent mutations that can be targeted in osteosarcoma. Here, we report that epigenetic changes via mRNA methylation holds great promise to better understand the mechanisms of osteosarcoma growth and to develop targeted therapeutics. In patients with osteosarcoma, the RNA demethylase ALKBH5 was amplified and higher expression correlated with copy-number changes. ALKBH5 was critical for promoting osteosarcoma growth and metastasis, yet it was dispensable for normal cell survival. Methyl RNA immunoprecipitation sequencing analysis and functional studies showed that ALKBH5 mediates its protumorigenic function by regulating m6A levels of histone deubiquitinase USP22 and the ubiquitin ligase RNF40. ALKBH5-mediated m6A deficiency in osteosarcoma led to increased expression of USP22 and RNF40 that resulted in inhibition of histone H2A monoubiquitination and induction of key protumorigenic genes, consequently driving unchecked cell-cycle progression, incessant replication, and DNA repair. RNF40, which is historically known to ubiquitinate H2B, inhibited H2A ubiquitination in cancer by interacting with and affecting the stability of DDB1-CUL4–based ubiquitin E3 ligase complex. Taken together, this study directly links increased activity of ALKBH5 with dysregulation of USP22/RNF40 and histone ubiquitination in cancers. More broadly, these results suggest that m6A RNA methylation works in concert with other epigenetic mechanisms to control cancer growth. Significance: RNA demethylase ALKBH5 upregulates USP22 and RNF40 to inhibit histone H2A ubiquitination and induces expression of key replication and DNA repair–associated genes, driving osteosarcoma progression.

Opioid addiction remains a severe health problem. While substantial insights underlying opioid addiction have been yielded from neuron-centric studies, the contribution of non-neuronal mechanisms to opioid-related behavioral adaptations has begun to be recognized. Toll-like receptor 4 (TLR4), a pattern recognition receptor, has been widely suggested in opioid-related behaviors. Interleukin-1 receptor-associated kinase 4 (IRAK4) is a kinase essential for TLR4 responses, However, the potential role of IRAK4 in opioid-related responses has not been examined. Here, we explored the role of IRAK4 in cue-induced opioid-seeking behavior in male rats. We found that morphine self-administration increased the phosphorylation level of IRAK4 in the nucleus accumbens (NAc) in rats; the IRAK4 signaling remained activated after morphine extinction and cue-induced reinstatement test. Both systemic and local inhibition of IRAK4 in the NAc core attenuated cue-induced morphine-seeking behavior without affecting the locomotor activity and cue-induced sucrose-seeking. In addition, inhibition of IRAK4 also reduced the cue-induced reinstatement of fentanyl-seeking. Our findings suggest an important role of IRAK4 in opioid relapse-like behaviors and provide novel evidence in the association between innate immunity and drug addiction.

Northern corn leaf blight (NCLB) caused by Setosphaeria turcica is one of the most devastating foliar diseases in maize (Zea mays L.), resulting in great economic losses worldwide. The mutation of the pathogen exacerbates the occurrence and harmfulness of NCLB in China. Therefore, there is an urgent need for evaluating and cultivating resistant hybrids. Here, the response of 239 maize hybrids approved in Northeast China to NCLB was evaluated during 2019 and 2020. The results showed that 92 (38.49%) and 75 (31.38%) hybrids were rated as moderately resistant and resistant, respectively, which together constituted the predominant resistant categories. We observed that maize hybrids from different certified sources had different levels of resistance to NCLB, whose disease parameter values varied significantly (P < 0.05) among 52 main cultivated hybrids. In 2019 and 2020, the average size of the lesions increased from 21.02 to 21.06 cm2, the average lesion density decreased from 1.36 to 1.33 lesions/100 cm2, and more than 30% of the hybrids registered final disease severity scores between 10 and 30%. The area under the disease progress curve of the main cultivated hybrids ranged from 57.96 to 986.86 cm2 in 2019 and from 50.75 to 1,028.65 cm2 in 2020. Correlation analysis revealed a significant relationship (P < 0.0001) among four disease parameters. Current research has shown that many maize hybrids in Northeast China are resistant to NCLB, suggesting that the large-scale cultivation of susceptible hybrids has led to the occurrence and prevalence of the disease. This study should assist growers in purposefully selecting resistant commercial hybrids to contribute to the management of NCLB.

An all-solid Z-scheme heterojunction TiO2–TiC/g-C3N4 was proposed and synthesized successfully by a facile calcination method and used for photocatalytic CO2 reduction in the presence of CH4.

Despite intensive studies during the last 3 years, the pathology and underlying molecular mechanism of coronavirus disease 2019 (COVID-19) remain poorly defined. Here, we examined postmortem COVID-19 lung tissues by spatial single-cell transcriptome analysis (SSCTA). We identified 18 major parenchymal and immune cell types, all of which are infected by SARS-CoV-2. Compared to the non-COVID-19 control, COVID-19 lungs have reduced alveolar cells (ACs), and increased innate and adaptive immune cells. Additionally, 19 differentially expressed genes in both infected and uninfected cells across the tissues mirror the altered cellular compositions. Spatial analysis of local infection rates revealed regions with high infection rates that are correlated with high cell densities (HIHD). The HIHD regions express high levels of SARS-CoV-2 entry-related factors including ACE2, FURIN, TMPRSS2, and NRP1, and co-localized with organizing pneumonia (OP) and lymphocytic and immune infiltration that have increased ACs and fibroblasts but decreased vascular endothelial cells and epithelial cells, echoing the tissue damage and wound healing processes. Sparse non- negative matrix factorization (SNMF) analysis of neighborhood cell type composition (NCTC) features identified 7 signatures that capture structure and immune niches in COVID-19 tissues. Trajectory inference based on immune niche signatures defined two pathological routes. Trajectory A progresses with primarily increased NK cells and granulocytes, likely reflecting the complication of microbial infections. Trajectory B is marked by increased HIHD and OP, possibly accounting for the increased immune infiltration. The OP regions are marked by high numbers of fibroblasts expressing extremely high levels of COL1A1 and COL1A2. Examination of single-cell RNA-seq data (scRNA-seq) from COVID-19 lung tissues and idiopathic pulmonary fibrosis (IPF) identified similar cell populations primarily consisting of myofibroblasts.Immunofluorescence staining revealed the activation of IL6-STAT3 and TGF-²-SMAD2/3 pathways in these cells, which likely mediate the upregulation of COL1A1 and COL1A2, and excessive fibrosis in the lung tissues. Together, this study provides an SSCTA atlas of cellular and molecular signatures of fatal COVID-19 lungs, revealing the complex spatial cellular heterogeneity, organization, and interactions that characterized the COVID-19 lung pathology.

Since the report of the first COVID-19 case in 2019, SARS-CoV-2 variants of concern (VOCs) have continued to emerge, manifesting diverse infectivity, evasion of host immunity and pathology. While ACE2 is the predominant receptor of SARS-CoV-2, TMPRSS2, Kim-1, NRP-1, CD147, furin, CD209L, and CD26 have also been implicated as viral entry-related cofactors. To understand the variations in infectivity and pathogenesis of VOCs, we conducted infection analysis in human cells from different organ systems using pseudoviruses of VOCs including Alpha, Beta, Gamma, and Delta. Recombinant spike S1, RBD, ACE2, Kim-1, and NRP-1 proteins were tested for their ability to block infection to dissect their roles in SARS-CoV-2 entry into cells. Compared with wild type SARS-CoV-2 (WT), numerous VOCs had significant increases of infectivity across a wide spectrum of cell types. Recombinant ACE2 protein more effectively inhibited the infection of VOCs including Delta and Omicron (BA.1 and BA.2) than that of WT. Interestingly, recombinant S1, RBD, Kim-1, and NRP-1 proteins inhibited the infection of all pseudoviruses in a manner dependent on the levels of ACE2 expression in different cell types. These results provide insights into the diverse infectivity of SARS-CoV-2 VOCs, which might be helpful for managing the emergence of new VOCs.

Mixed sedimentation is mainly a phenomenon by which siliciclastic and carbonate are mixed under a similar sedimentary environment. The study of the composition of mixed rock can reflect the sedimentary environment. The mixed sediments of the Canglangpu formation in the eastern Sichuan basin are widely developed and exhibit well exploration prospects. In this study, a classification diagram of mixed sediments suitable for the Canglangpu formation was proposed by combining lithologic characteristics with logging data. Based on the observations of typical outcrop profiles, the identification of thin sections, and drilling and geological logging data, a model was established to identify the electrical responses of the mixed sedimentary rocks in the study area. The results show that (1) the Canglangpu formation can be vertically divided into two complete transgression-regression cycles with the lower part mainly consisting of sedimentary carbonate diamictite and the upper part principally composed of clastic diamictite; (2) mixed sediments in the Canglangpu formation can be divided into six classes, namely carbonate sandstone, argillaceous sandstone, sandy carbonate rock, argillaceous carbonate rock, sandy mudstone, and Carbonate mudstone; (3) the sedimentary environment of the Canglangpu formation be divided into (a) mixed sediments in the shore, which include mixed lagoon and mixed tidal flat, (b) mixed sediments in the shallow marine shelf, which includes mixed beach bar, terrigenous detrital mixed shelf, and carbonate mixed shelf; (4) a mixed shore-mixed shelf sedimentary model has been established; it says that the mixed sediments show obvious characteristics of ring-like development around underwater paleo-heights. The formation mechanism of mixed sedimentation in the eastern Sichuan basin is mainly controlled by the change of sedimentary facies belt, and the development intensity is mainly influenced by early tectonic movement and sea-level change.

Mitogen-activated protein kinases (MAPKs) play critical roles in the induction of numerous cytokines, chemokines, and inflammatory mediators that mobilize the immune system to counter pathogenic infections. Dual-specificity phosphatase-1 (DUSP1) is a member of dual-specificity phosphatases, which inactivates MAPKs through a negative feedback mechanism. Here we report that in response to viral and bacterial infections, not only DUSP1 transcript but also itsN6-methyladenosine (m6A) level rapidly increase together with the m6A reader protein YTHDF2, resulting in enhanced YTHDF2-mediated DUSP1 transcript degradation. Knockdown of DUSP1 promotes p38 and JNK phosphorylation and activation, thus increasing the expression of innate immune response genes including IL1β, CSF3, TGM2 and SRC. Similarly, knockdown of m6A eraser ALKBH5 increases DUSP1 transcript m6A level resulting in accelerated transcript degradation, activation of p38 and JNK, and enhanced expression of IL1β, CSF3, TGM2 and SRC. These results demonstrate that m6A and reader protein YTHDF2 orchestrate optimal innate immune response during viral and bacterial infections by downregulating the expression of a negative regulator DUSP1 of the p38 and JNK pathways that are central to innate immune response against pathogenic infections.IMPORTANCEInnate immunity is central for controlling pathogenic infections and maintaining the homeostasis of the host. In this study, we have revealed a novel mechanism regulating innate immune response during viral and bacterial infections. We have found thatN6-methyladenosine (m6A) and the reader protein YTHDF2 regulate dual-specificity phosphatase-1, a negative regulator of mitogen-activated protein kinases p38 and JNK, to maximize innate immune response during viral and bacterial infections. These results provide novel insights into the mechanism regulating innate immunity, which could help the development of novel approaches for controlling pathogenic infections.

Purpose: The favorable prognosis of stage I and II nasopharyngeal carcinoma (NPC) has motivated a search for biomarkers for the early detection and risk assessment of Epstein-Barr virus (EBV)–associated NPC. Although EBV seropositivity is ubiquitous among adults, a spike in antibodies against select EBV proteins is a harbinger of NPC. A serologic survey would likely reveal which EBV antibodies could discriminate those at risk of developing NPC. Experimental Design: Lysates from a new EBV mammalian expression library were used in a denaturing multiplex immunoblot assay to survey antibodies against EBV in sera collected from healthy individuals who later developed NPC (incident cases) in a prospective cohort from Singapore and validated in an independent cohort from Shanghai, P.R. China. Results: We show that IgA against EBV nuclear antigen 1 (EBNA1) discriminated incident NPC cases from matched controls with 100% sensitivity and 100% specificity up to 4 years before diagnosis in both Singapore and Shanghai cohorts. Incident NPC cases had a greater IgG repertoire against lytic-classified EBV proteins, and the assortment of IgA against EBV proteins detected by the immunoblot assay increased closer to diagnosis. Conclusions: Although NPC tumors consistently harbor latent EBV, the observed heightened systemic and mucosal immunity against lytic-classified antigens years prior to clinical diagnosis is consistent with enhanced lytic transcription. We conclude that an expanding EBV mucosal reservoir (which can be latent and/or lytic) is a risk factor for NPC. This presents an opportunity to identify those at risk of developing NPC using IgA against EBNA1 as a biomarker.