Human antibody C10 neutralizes by diminishing Zika but enhancing dengue virus dynamics.

The human monoclonal antibody (HmAb) C10 potently cross-neutralizes Zika virus (ZIKV) and dengue virus. Analysis of antibody fragment (Fab) C10 interactions with ZIKV and dengue virus serotype 2 (DENV2) particles by cryoelectron microscopy (cryo-EM) and amide hydrogen/deuterium exchange mass spectrometry (HDXMS) shows that Fab C10 binding decreases overall ZIKV particle dynamics, whereas with DENV2, the same Fab causes increased dynamics. Testing of different Fab C10:DENV2 E protein molar ratios revealed that, at higher Fab ratios, especially at saturated concentrations, the Fab enhanced viral dynamics (detected by HDXMS), and observation under cryo-EM showed increased numbers of distorted particles. Our results suggest that Fab C10 stabilizes ZIKV but that with DENV2 particles, high Fab C10 occupancy promotes E protein dimer conformational changes leading to overall increased particle dynamics and distortion of the viral surface. This is the first instance of a broadly neutralizing antibody eliciting virus-specific increases in whole virus particle dynamics.

Structure and neutralization mechanism of a human antibody targeting a complex Epitope on Zika virus.

We currently have an incomplete understanding of why only a fraction of human antibodies that bind to flaviviruses block infection of cells. Here we define the footprint of a strongly neutralizing human monoclonal antibody (mAb G9E) with Zika virus (ZIKV) by both X-ray crystallography and cryo-electron microscopy. Flavivirus envelope (E) glycoproteins are present as homodimers on the virion surface, and G9E bound to a quaternary structure epitope spanning both E protomers forming a homodimer. As G9E mainly neutralized ZIKV by blocking a step after viral attachment to cells, we tested if the neutralization mechanism of G9E was dependent on the mAb cross-linking E molecules and blocking low-pH triggered conformational changes required for viral membrane fusion. We introduced targeted mutations to the G9E paratope to create recombinant antibodies that bound to the ZIKV envelope without cross-linking E protomers. The G9E paratope mutants that bound to a restricted epitope on one protomer poorly neutralized ZIKV compared to the wild-type mAb, demonstrating that the neutralization mechanism depended on the ability of G9E to cross-link E proteins. In cell-free low pH triggered viral fusion assay, both wild-type G9E, and epitope restricted paratope mutant G9E bound to ZIKV but only the wild-type G9E blocked fusion. We propose that, beyond antibody binding strength, the ability of human antibodies to cross-link E-proteins is a critical determinant of flavivirus neutralization potency.

TRIM21 is critical in regulating hepatocellular carcinoma growth and response to therapy by altering the MST1/YAP pathway.

Liver cancer is the sixth most common cancer and the third leading cause of cancer-related death globally. Despite efforts being made in last two decades in cancer diagnosis and treatment, the 5-year survival rate of liver cancer remains extremely low. TRIM21 participates in cancer metabolism, glycolysis, immunity, chemosensitivity and metastasis by targeting various substrates for ubiquitination. TRIM21 serves as a prognosis marker for human hepatocellular carcinoma (HCC), but the mechanism by which TRIM21 regulates HCC tumorigenesis and progression remains elusive. In this study, we demonstrated that TRIM21 protein levels were elevated in human HCC. Elevated TRIM21 expression was associated with HCC progression and poor survival. Knockdown of TRIM21 in HCC cell lines significantly impaired cell growth and metastasis and enhanced sorafenib-induced toxicity. Mechanistically, we found that knockdown of TRIM21 resulted in cytosolic translocation and inactivation of YAP. At the molecular level, we further identified that TRIM21 interacted and induced ubiquitination of MST1, which resulted in MST1 degradation and YAP activation. Knockdown of MST1 or overexpression of YAP reversed TRIM21 knockdown-induced impairment of HCC growth and chemosensitivity. Taken together, the current study demonstrates a novel mechanism that regulates the Hippo pathway and reveals TRM21 as a critical factor that promotes growth and chemoresistance in human HCC.

The genetic and biological characterization of the first avian paramyxovirus serotype 14 isolated from chicken in China.

In October 2020, an avian paramyxovirus serotype 14 (APMV-14)-designated chicken/Fujian/2160/2020 (FJ2160) was isolated from tracheal and cloacal swab sample of chicken collected from live bird market in Fujian province in China during the active surveillance program. The complete genome of FJ2160 comprised 15,444 nucleotides (nt) complying with the paramyxovirus "rule of six" and encoded six non-overlapping structural proteins in the order of 3'-NP-P-M-F-HN-L-'5. The complete genome sequence analysis showed that FJ2160 had the highest identity (90.0%) with the APMV-14 isolated from Japan, while the nucleotide sequence identities of FJ2160 and other APMVs ranged from 42.4 to 51.1%. The F protein cleavage site was TREGR↓L, which resembled a lentogenic strain of APMV-1. Phylogenetic analysis revealed that the FJ2160 closest relative was APMV-14. The intracerebral pathogenicity index (ICPI) tests indicated that the virus was lentogenic. This is the first report of APMV-14 in China. These results provide evidence that APMV-14 could infect chickens and reveal the genetic characteristics and biological properties of the virus, which can help to better understand this new emerging APMV-14.

Interactions in Ammonia and Hydrogen Oxidation Examined in a Flow Reactor and a Shock Tube.

Ammonia (NH3) is a promising fuel, because it is carbon-free and easier to store and transport than hydrogen (H2). However, an ignition enhancer such as H2 might be needed for technical applications, because of the rather poor ignition properties of NH3. The combustion of pure NH3 and H2 has been explored widely. However, for mixtures of both gases, mostly only global parameters such as ignition delay times or flame speeds were reported. Studies with extensive experimental species profiles are scarce. Therefore, we experimentally investigated the interactions in the oxidation of different NH3/H2 mixtures in the temperature range of 750-1173 K at 0.97 bar in a plug-flow reactor (PFR), as well as in the temperature range of 1615-2358 K with an average pressure of 3.16 bar in a shock tube. In the PFR, temperature-dependent mole fraction profiles of the main species were obtained via electron ionization molecular-beam mass spectrometry (EI-MBMS). Additionally, for the first time, tunable diode laser absorption spectroscopy (TDLAS) with a scanned-wavelength method was adapted to the PFR for the quantification of nitric oxide (NO). In the shock tube, time-resolved NO profiles were also measured by TDLAS using a fixed-wavelength approach. The experimental results both in PFR and shock tube reveal the reactivity enhancement by H2 on ammonia oxidation. The extensive sets of results were compared with predictions by four NH3-related reaction mechanisms. None of the mechanisms can well predict all experimental results, but the Stagni et al. [React. Chem. Eng. 2020, 5, 696-711] and Zhu et al. [Combust. Flame 2022, 246, 115389] mechanisms perform best for the PFR and shock tube conditions, respectively. Exploratory kinetic analysis was conducted to identify the effect of H2 addition on ammonia oxidation and NO formation, as well as sensitive reactions in different temperature regimes. The results presented in this study can provide valuable information for further model development and highlight relevant properties of H2-assisted NH3 combustion.

Exploring the Effect of Different Reactivity Promoters on the Oxidation of Ammonia in a Jet-Stirred Reactor.

The low reactivity of ammonia (NH3) is the main barrier to applying neat NH3 as fuel in technical applications, such as internal combustion engines and gas turbines. Introducing combustion promoters as additives in NH3-based fuel can be a feasible solution. In this work, the oxidation of ammonia by adding different reactivity promoters, i.e., hydrogen (H2), methane (CH4), and methanol (CH3OH), was investigated in a jet-stirred reactor (JSR) at temperatures between 700 and 1200 K and at a pressure of 1 bar. The effect of ozone (O3) was also studied, starting from an extremely low temperature (450 K). Species mole fraction profiles as a function of the temperature were measured by molecular-beam mass spectrometry (MBMS). With the help of the promoters, NH3 consumption can be triggered at lower temperatures than in the neat NH3 case. CH3OH has the most prominent effect on enhancing the reactivity, followed by H2 and CH4. Furthermore, two-stage NH3 consumption was observed in NH3/CH3OH blends, whereas no such phenomenon was found by adding H2 or CH4. The mechanism constructed in this work can reasonably reproduce the promoting effect of the additives on NH3 oxidation. The cyanide chemistry is validated by the measurement of HCN and HNCO. The reaction CH2O + NH2 ⇄ HCO + NH3 is responsible for the underestimation of CH2O in NH3/CH4 fuel blends. The discrepancies observed in the modeling of NH3 fuel blends are mainly due to the deviations in the neat NH3 case. The total rate coefficient and the branching ratio of NH2 + HO2 are still controversial. The high branching fraction of the chain-propagating channel NH2 + HO2 ⇄ H2NO + OH improves the model performance under low-pressure JSR conditions for neat NH3 but overestimates the reactivity for NH3 fuel blends. Based on this mechanism, the reaction pathway and rate of production analyses were conducted. The HONO-related reaction routine was found to be activated uniquely by adding CH3OH, which enhances the reactivity most significantly. It was observed from the experiment that adding ozone to the oxidant can effectively initiate NH3 consumption at temperatures below 450 K but unexpectedly inhibit the NH3 consumption at temperatures higher than 900 K. The preliminary mechanism reveals that adding the elementary reactions between NH3-related species and O3 is effective for improving the model performance, but their rate coefficients have to be refined.

Willingness to receive the COVID-19 vaccine among HIV positive men who have sex with men in China: a cross-sectional study.

BACKGROUND: People living with HIV(PLWH) are deemed more vulnerable to the SARS-CoV-2 infection than the uninfected population. Vaccination is an effective measure for COVID-19 control, yet, little knowledge exists about the willingness of men who have sex with men (MSM) living with HIV in China to be vaccinated. METHODS: This cross-sectional study evaluated the willingness of MSM living with HIV to receive COVID-19 vaccination in six cities of Guangdong, China, from July to September 2020. Factors associated with willingness to receive COVID-19 vaccination using multivariable logistic regression. RESULTS: In total, we recruited 944 HIV-positive MSM with a mean age of 29.2 ± 7.7 years. Of all participants, 92.4% of them were willing to receive the COVID-19 vaccine. Participants who were separated, divorced, or widowed (adjusted OR: 5.29, 95%CI: 1.02-27.48), had an annual income higher than 9,000 USD (adjusted OR: 1.70, 95%CI: 1.01-2.86), had ever taken an HIV self-test (adjusted OR: 1.78, 95%CI: 1.07-2.95), had ever disclosed sexual orientation to a doctor/nurse (adjusted OR: 3.16, 95%CI: 1.33-7.50), had ever disclosed sexual orientation to others besides their male partners (adjusted OR: 2.18, 95%CI: 1.29-3.69) were more willing to receive the vaccine. Sex with a female partner in the past six months decreased the likelihood of willingness to receive the vaccine (adjusted OR: 0.40, 95%CI: 0.17-0.95). Economic burden, worry that my health condition could not bear the risk of receiving COVID-19 vaccines, and concern that the vaccination would affect the immune status and antiretroviral therapy were the main reasons for unwillingness to receive vaccination. CONCLUSION: Our study showed that HIV-positive MSM had a high willingness to receive the COVID-19 vaccination. Targeted interventions such as health education should be conducted among MSM with HIV infection to enhance COVID-19 vaccine uptake.

Structural basis of Chikungunya virus inhibition by monoclonal antibodies.

Chikungunya virus (CHIKV) is an emerging viral pathogen that causes both acute and chronic debilitating arthritis. Here, we describe the functional and structural basis as to how two anti-CHIKV monoclonal antibodies, CHK-124 and CHK-263, potently inhibit CHIKV infection in vitro and in vivo. Our in vitro studies show that CHK-124 and CHK-263 block CHIKV at multiple stages of viral infection. CHK-124 aggregates virus particles and blocks attachment. Also, due to antibody-induced virus aggregation, fusion with endosomes and egress are inhibited. CHK-263 neutralizes CHIKV infection mainly by blocking virus attachment and fusion. To determine the structural basis of neutralization, we generated cryogenic electron microscopy reconstructions of Fab:CHIKV complexes at 4- to 5-Å resolution. CHK-124 binds to the E2 domain B and overlaps with the Mxra8 receptor-binding site. CHK-263 blocks fusion by binding an epitope that spans across E1 and E2 and locks the heterodimer together, likely preventing structural rearrangements required for fusion. These results provide structural insight as to how neutralizing antibody engagement of CHIKV inhibits different stages of the viral life cycle, which could inform vaccine and therapeutic design.

Complication rates and safety of pulsed dye laser treatment for port-wine stain: a systematic review and meta-analysis.

Pulsed dye laser (PDL) is the most commonly used method for port-wine stain (PWS); however, no studies have reported the safety of PDL. This review aimed to collect and summarize complications reported in relevant literature, assess complication rates in treating PWS with PDL, and explore the relevant influencing factors. A systematic review and meta-analysis were conducted to search for related studies in PubMed, Embase, and the Cochrane Library until August 2022. Two reviewers independently evaluated the risk of bias of included studies. Stata Software version 17.0 was used for the analysis. All complications reported in the literature are divided into acute phase complications and long-term complications. Overall pooled purpura, edema, crusting, blistering, hyperpigmentation, hypopigmentation, and scarring rates were 98.3%, 97.6%, 21.5%, 8.7%, 12.8%, 0.9%, and 0.2%, respectively. Although the acute adverse reactions were found to be common, the long-term permanent complications clearly have a lower frequency, and the occurrence of scarring is much lower than that initially thought. This indicates that effective protective measures after treatment are very important for preventing scar formation. Overall, PDL treatment for PWS shows a high level of safety and low chances of causing long-term complications.

Identification of tumor immunophenotypes associated with immunotherapy response in bladder cancer.

OBJECTIVES: This study aims to reveal immunophenotypes associated with immunotherapy response in bladder cancer, identify the signature genes of immune subtypes, and provide new molecular targets for improving immunotherapy response. METHODS: Bladder cancer immunophenotypes were characterized in the bulk RNA sequencing dataset GSE32894 and Imvigor210, and gene expression signatures were established to identify the immunophenotypes. Expression of gene signatures were validated in single-cell RNA sequencing dataset GSE145140 and human proteins expression data source. Investigation of Immunotherapy Response was performed in IMvigor210 dataset. Prognosis of tumor immunophenotypes was further analyzed. RESULTS: Inflamed and immune-excluded immunophenotypes were characterized based on the tumor immune cell scores. Risk score models that were established rely on RNA sequencing profiles and overall survival of bladder cancer cohorts. The inflamed tumors had lower risk scores, and the low-risk tumors were more likely to respond to atezolizumab, receiving complete response/partial response (CR/PR). Patients who responded to atezolizumab had higher SRRM4 and lower NPHS1 and TMEM72 expression than the non-responders. SRRM4 expression was a protective factor for bladder cancer prognosis, while the NPHS1 and TMEM72 showed the opposite pattern. CONCLUSION: This study provided a novel classification method for tumor immunophenotypes. Bladder cancer immunophenotypes can predict the response to immune checkpoint blockade. The immunophenotypes can be identified by the expression of signature genes.

Proteomic Difference Analysis of Whole Blood and Bloodstains.

OBJECTIVES: To study the changes of protein levels in peripheral blood after it dried. METHODS: The proteins from whole blood and bloodstains were detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and normalized by the label-free quantification (LFQ) method. The differential proteins were analyzed by using R 4.2.1 software, limma and edgeR package. The analysis of biological function, signaling pathway and subcellular localization for the differential proteins was then performed. RESULTS: A total of 623 and 596 proteins were detected in whole blood and bloodstains, respectively, of which 31 were statistically significant in the quantitative results, including 10 up-regulated and 21 down-regulated proteins in bloodstains. CONCLUSIONS: The protein abundances in whole blood and bloodstains are highly correlated, and the variation of protein abundances may be related to the changes of endogenous and structural proteins in cells. The application of proteomics technology can assist the screening and identification of protein biomarkers, thereby introducing new biomarkers for forensic research.

Multiplex Real-Time Reverse Transcription PCR for Influenza A Virus, Influenza B Virus, and Severe Acute Respiratory Syndrome Coronavirus 2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019, and the outbreak rapidly evolved into the current coronavirus disease pandemic. SARS-CoV-2 is a respiratory virus that causes symptoms similar to those caused by influenza A and B viruses. On July 2, 2020, the US Food and Drug Administration granted emergency use authorization for in vitro diagnostic use of the Influenza SARS-CoV-2 Multiplex Assay. This assay detects influenza A virus at 102.0, influenza B virus at 102.2, and SARS-CoV-2 at 100.3 50% tissue culture or egg infectious dose, or as few as 5 RNA copies/reaction. The simultaneous detection and differentiation of these 3 major pathogens increases overall testing capacity, conserves resources, identifies co-infections, and enables efficient surveillance of influenza viruses and SARS-CoV-2.

Structural and Functional Characterization of the Phosphoprotein Central Domain of Spring Viremia of Carp Virus.

Spring viremia of carp virus (SVCV) is a highly pathogenic Vesiculovirus in the common carp. The phosphoprotein (P protein) of SVCV is a multifunctional protein that acts as a polymerase cofactor and an antagonist of cellular interferon (IFN) response. Here, we report the 1.5-Å-resolution crystal structure of the P protein central domain (PCD) of SVCV (SVCVPCD). The PCD monomer consists of two ß sheets, an α helix, and another two ß sheets. Two PCD monomers pack together through their hydrophobic surfaces to form a dimer. The mutations of residues on the hydrophobic surfaces of PCD disrupt the dimer formation to different degrees and affect the expression of host IFN consistently. Therefore, the oligomeric state formation of the P protein of SVCV is an important mechanism to negatively regulate host IFN response.IMPORTANCE SVCV can cause spring viremia of carp with up to 90% lethality, and it is the homologous virus of the notorious vesicular stomatitis virus (VSV). There are currently no drugs that effectively cure this disease. P proteins of negative-strand RNA viruses (NSVs) play an essential role in many steps during the replication cycle and an additional role in immunosuppression as a cofactor. All P proteins of NSVs are oligomeric, but the studies on the role of this oligomerization mainly focus on the process of virus transcription or replication, and there are few studies on the role of PCD in immunosuppression. Here, we present the crystal structure of SVCVPCD A new mechanism of immune evasion is clarified by exploring the relationship between SVCVPCD and host IFN response from a structural biology point of view. These findings may provide more accurate target sites for drug design against SVCV and provide new insights into the function of NSVPCD.

Spring viraemia of carp virus modulates p53 expression using two distinct mechanisms.

p53, which regulates cell-cycle arrest and apoptosis, is a crucial target for viruses to release cells from cell-cycle checkpoints or to protect cells from apoptosis for their own benefit. Viral evasion mechanisms of aquatic viruses remain mysterious. Here, we report the spring viremia of carp virus (SVCV) degrading and stabilizing p53 in the ubiquitin-proteasome pathway by the N and P proteins, respectively. Early in an SVCV infection, significant induction was observed in the S phase and p53 was decreased in the protein level. Further experiments demonstrated that p53 interacted with SVCV N protein and was degraded by suppressing the K63-linked ubiquitination. However, the increase of p53 was observed late in the infection and experiments suggested that p53 was bound to SVCV P protein and stabilized by enhancing the K63-linked ubiquitination. Finally, lysine residue 358 was the key site for p53 K63-linked ubiquitination by the N and P proteins. Thus, our findings suggest that fish p53 is modulated by SVCV N and P protein in two distinct mechanisms, which uncovers the strategy for the subversion of p53-mediated host innate immune responses by aquatic viruses.

HSPB8 promoted intrahepatic cholangiocarcinoma progression by enhancing epithelial-mesenchymal transition and autophagy.

PURPOSE: Heat shock protein B8 (HSPB8) has been recently discovered to be participated in the regulation of tumor progression. However, the function of HSPB8 in intrahepatic cholangiocarcinoma (ICC) has not yet been elucidated. This study studied the function of HSPB8 in ICC progression. METHODS: ICC patients (n = 150) were enrolled. The relationship between clinicopathological characteristics and HSPB8 expression was analyzed. RBE cells were transfected and treated by 3-MA. The RBE cells morphology was observed under a transmission electron microscope. Cell counting kit-8 assay, wound healing assay and Transwell experiment was conducted to detect RBE cells proliferation, migration and invasion. Quantitative reverse transcription-polymerase chain reaction, immunohistochemistry, Western blot and immunofluorescence were used for genes detection in clinical tissues and RBE cells. RESULTS: HSPB8 was up-regulated in ICC tissues than that in adjacent normal tissues. High HSPB8 expression in ICC indicated poor prognosis of patients. HSPB8 expression was mainly expressed in cell cytoplasm and aberrantly increased in RBE cells (P < 0.01). HSPB8 up-regulation promoted RBE cells proliferation, migration and invasion (P < 0.05). HSPB8 down-regulation reduced RBE cells proliferation, migration and invasion (P < 0.01). HSPB8 overexpression facilitated Vimentin expression, LC3-II/LC3-I ratio and inhibited E-cadherin, p62 expression in RBE cells (P < 0.05). Treatment of 3-MA partially reversed HSPB8 promotion on RBE cells proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) (P < 0.05 or P < 0.01). CONCLUSION: HSPB8 promoted ICC progression by enhancing EMT and autophagy. HSPB8 might be an effective target for ICC treatment.

Zebrafish NDRG1a Negatively Regulates IFN Induction by Promoting the Degradation of IRF7.

Viral infection activates the transcription factor IFN regulatory factor 7 (IRF7), which plays a critical role in the induction of IFNs and innate antiviral immune response. How virus-induced IFN signaling is controlled in fish is not fully understood. In this study, we demonstrate that N-myc downstream-regulated gene 1a (NDRG1a) in zebrafish plays a role as a negative regulator for virus-triggered IFN induction. First, the activation of the IFN promoter stimulated by the polyinosinic-polycytidylic acid or spring viremia of carp virus was decreased by the overexpression of NDRG1a. Second, NDRG1a interacted with IRF7 and blocked the IFN transcription activated by IRF7. Furthermore, NDRG1a was phosphorylated by TANK-binding kinase 1 (TBK1) and promoted the K48-linked ubiquitination and degradation of IRF7. Finally, the overexpression of NDRG1a blunted the transcription of several IFN-stimulated genes, resulting in the host cells becoming susceptible to spring viremia of carp virus infection. Our findings suggest that fish NDRG1a negatively regulates the cellular antiviral response by targeting IRF7 for ubiquitination and degradation, providing insights into the novel role of NDRG1a on the innate antiviral immune response in fish.

Clinical characteristics and risk factors associated with COVID-19 disease severity in patients with cancer in Wuhan, China: a multicentre, retrospective, cohort study.

BACKGROUND: COVID-19 has spread globally. Epidemiological susceptibility to COVID-19 has been reported in patients with cancer. We aimed to systematically characterise clinical features and determine risk factors of COVID-19 disease severity for patients with cancer and COVID-19. METHODS: In this multicentre, retrospective, cohort study, we included all adult patients (aged ≥18 years) with any type of malignant solid tumours and haematological malignancy who were admitted to nine hospitals in Wuhan, China, with laboratory-confirmed COVID-19 between Jan 13 and March 18, 2020. Enrolled patients were statistically matched (2:1) with patients admitted with COVID-19 who did not have cancer with propensity score on the basis of age, sex, and comorbidities. Demographic characteristics, laboratory examinations, illness severity, and clinical interventions were compared between patients with COVID-19 with or without cancer as well as between patients with cancer with non-severe or severe COVID-19. COVID-19 disease severity was defined on admission on the basis of the WHO guidelines. Univariable and multivariable logistic regression, adjusted for age, sex, comorbidities, cancer type, tumour stage, and antitumour treatments, were used to explore risk factors associated with COVID-19 disease severity. This study was registered in the Chinese Clinical Trial Register, ChiCTR2000030807. FINDINGS: Between Jan 13 and March 18, 2020, 13 077 patients with COVID-19 were admitted to the nine hospitals in Wuhan and 232 patients with cancer and 519 statistically matched patients without cancer were enrolled. Median follow-up was 29 days (IQR 22-38) in patients with cancer and 27 days (20-35) in patients without cancer. Patients with cancer were more likely to have severe COVID-19 than patients without cancer (148 [64%] of 232 vs 166 [32%] of 519; odds ratio [OR] 3·61 [95% CI 2·59-5·04]; p<0·0001). Risk factors previously reported in patients without cancer, such as older age; elevated interleukin 6, procalcitonin, and D-dimer; and reduced lymphocytes were validated in patients with cancer. We also identified advanced tumour stage (OR 2·60, 95% CI 1·05-6·43; p=0·039), elevated tumour necrosis factor α (1·22, 1·01-1·47; p=0·037), elevated N-terminal pro-B-type natriuretic peptide (1·65, 1·03-2·78; p=0·032), reduced CD4+ T cells (0·84, 0·71-0·98; p=0·031), and reduced albumin-globulin ratio (0·12, 0·02-0·77; p=0·024) as risk factors of COVID-19 severity in patients with cancer. INTERPRETATION: Patients with cancer and COVID-19 were more likely to deteriorate into severe illness than those without cancer. The risk factors identified here could be helpful for early clinical surveillance of disease progression in patients with cancer who present with COVID-19. FUNDING: China National Natural Science Foundation.

Identification, expression, and artificial selection of silkworm epigenetic modification enzymes.

BACKGROUND: Understanding the genetic basis of phenotype variations during domestication and breeding is of great interest. Epigenetics and epigenetic modification enzymes (EMEs) may play a role in phenotypic variations; however, no comprehensive study has been performed to date. Domesticated silkworm (Bombyx mori) may be utilized as a model in determining how EMEs influence domestication traits. RESULTS: We identified 44 EMEs in the genome of silkworm (Bombyx mori) using homology searching. Phylogenetic analysis showed that genes in a subfamily among different animals were well clustered, and the expression pattern of EMEs is constant among Bombyx mori, Drosophila melanogaster, and Mus musculus. These are most highly expressed in brain, early embryo, and internal genitalia. By gene-related selective sweeping, we identified five BmEMEs under artificial selection during the domestication and breeding of silkworm. Among these selected genes, BmSuv4-20 and BmDNMT2 harbor selective mutations in their upstream regions that alter transcription factor-binding sites. Furthermore, these two genes are expressed higher in the testis and ovary of domesticated silkworm compared to wild silkworms, and correlations between their expression pattern and meiosis of the sperm and ova were observed. CONCLUSIONS: The domestication of silkworm has induced artificial selection on epigenetic modification markers that may have led to phenotypic changes during domestication. We present a novel perspective to understand the genetic basis underlying animal domestication and breeding.

Zebrafish RPZ5 Degrades Phosphorylated IRF7 To Repress Interferon Production.

Interferon (IFN) production activated by phosphorylated interferon regulatory factor 7 (IRF7) is a pivotal process during host antiviral infection. For viruses, suppressing the host IFN response is beneficial for viral proliferation; in such cases, evoking host-derived IFN negative regulators would be very useful for viruses. Here, we report that the zebrafish rapunzel 5 (RPZ5) protein which activated by virus degraded phosphorylated IRF7 is activated by TANK-binding kinase 1 (TBK1), leading to a reduction in IFN production. Upon viral infection, zebrafish rpz5 was significantly upregulated, as was ifn, in response to the stimulation. Overexpression of RPZ5 blunted the IFN expression induced by both viral and retinoic acid-inducible gene I (RIG-I) like-receptor (RLR) factors. Subsequently, RPZ5 interacted with RLRs but did not affect the stabilization of the proteins in the normal state. Interestingly, RPZ5 degraded the phosphorylated IRF7 under TBK1 activation through K48-linked ubiquitination. Finally, the overexpression of RPZ5 remarkably reduced the host cell antiviral capacity. These findings suggest that zebrafish RPZ5 is a negative regulator of phosphorylated IRF7 and attenuates IFN expression during viral infection, providing insight into the IFN balance mechanism in fish.IMPORTANCE The phosphorylation of IRF7 is helpful for host IFN production to defend against viral infection; thus, it is a potential target for viruses to mitigate the antiviral response. We report that the fish RPZ5 is an IFN negative regulator induced by fish viruses and degrades the phosphorylated IRF7 activated by TBK1, leading to IFN suppression and promotion of viral proliferation. These findings reveal a novel mechanism for interactions between the host cell and viruses in the lower vertebrate.

miR-874 inhibits gastric cancer cell proliferation by targeting SPAG9.

BACKGROUND: microRNAs (miRNAs) play essential roles in the development and progression of gastric cancer (GC). Although aberrant miR-874 expression has been reported in various human cancers, its role in GC remains obscure. METHODS: miR-874 expression was assessed by real-time quantitative polymerase chain reaction (RT-qPCR) in 62 matched GC and adjacent normal tissues, as well as in GC cell lines and immortalized human gastric epithelial cells. CCK8 assay, colony formation assay, and flow cytometry were used to assess the role of miR-874 in GC cell proliferation and apoptosis in vitro. Additionally, to determine the effects of miR-874 on GC cell proliferation and apoptosis in vivo, BALB/c nude mice were injected with GC cells transfected with a miR-874 mimic. The role of miR-874 in SPAG9 expression was assessed by luciferase assay, Western blotting, and RT-qPCR. RESULTS: miR-874 was downregulated in GC cell lines and tissues. miR-874 overexpression in GC cells led to inhibition of cell proliferation and induction of apoptosis. Moreover, SPAG9 was identified as a direct miR-874 target, the expression of which was suppressed by miR-874. SPAG9 overexpression markedly promoted GC cell proliferation. CONCLUSIONS: miR-874 inhibited cell proliferation and induced apoptosis in GC cells. SPAG9 downregulation was crucial for the tumor-suppressive effects of miR-874. Hence, the miR-874/SPAG9 axis could serve as a novel therapeutic target in GC.