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The newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant, sublineages BA.1 and BA.2, recently became the dominant variants of concern (VOCs) with significantly higher transmissibility than any other variant appeared and markedly greater resistance to neutralization antibodies and original ancestral WA1 spike-matched vaccine. Therefore, it is urgent to develop vaccines against VOCs like Omicron. Unlike the new booming messenger RNA (mRNA) vaccine, protein vaccines have been used for decades to protect people from various kinds of viral infections and have advantages with their inexpensive production protocols and their relative stability in comparison to the mRNA vaccine. Here, we show that sera from BA.1 spike protein vaccinated mice mainly elicited neutralizing antibodies against BA.1 itself. However, a booster with BA.1 spike protein or a bivalent vaccine composed of D614G and BA.1 spike protein-induced not only potent neutralizing antibody response against D614G and BA.1 pseudovirus, but also against BA.2, other four SARS-CoV-2 VOCs (Alpha, Beta, Gamma, and Delta) and SARS-CoV-2-related coronaviruses (pangolin CoV GD-1 and bat CoV RsSHC014). The two recombinant spike protein vaccines method described here lay a foundation for future vaccine development for broad protection against pan-sarbecovirus.
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Vacinas contra COVID-19 , COVID-19 , Glicoproteína da Espícula de Coronavírus , Animais , Anticorpos Neutralizantes , Anticorpos Antivirais , COVID-19/prevenção & controle , Vacinas contra COVID-19/imunologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinas Combinadas , Vacinas Sintéticas/imunologia , Vacinas de mRNA/imunologiaRESUMO
Aim: Marital status has been proved a significant prognostic factor for diagnosis and prognosis in various cancers, but the effect in endometrial cancer (EMC) is controversial. The research was designed to clarify the relationship between marital status and EMC. Methods: We identified 39,387 patients with EMC between 2004 and 2010 from the Surveillance Epidemiology and End Results database. Patients were categorized into four groups according to marital status. We used the logistic regression, the Kaplan-Meier method and Cox regression analysis to analyze the effect of marital status on EMC-related diagnosis and prognosis. Results: The study suggests that marriage benefits the diagnosis and prognosis of EMC. Widowed and unmarried patients had higher risk of mortality than other marital status.
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Neoplasias do Endométrio/mortalidade , Estado Civil/estatística & dados numéricos , Programa de SEER/estatística & dados numéricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/terapia , Endométrio/patologia , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Fatores de Risco , Resultado do Tratamento , Estados Unidos/epidemiologia , Adulto JovemRESUMO
The DNA polymerase delta (Pol δ), a heterotetramer of four subunits (Pol δ4), plays a pivotal role in DNA replication, as well as in DNA damage repair. Pold4, as the smallest subunit of Pol δ, is degraded in response to DNA damage or when entering into S-phase. This leads to the conversion of Pol δ4 to the trimeric complex Pol δ3. However, the contribution of Pold4 has not been fully elucidated in mammals. Cdm1, the Pold4 ortholog in Schizosaccharomyces pombe, is dispensable for cell growth and DNA damage repair, and there are no Pold4 orthologs in Saccharomyces cerevisiae. We previously generated a knockout mouse model of Pold3 and revealed its essential role in genome stability. Unexpectedly, we here found that Pold4 knockout mice are viable and fertile. In addition, Pold4 knockout mice do not exhibit any pathologic changes in the lung and spleen, tissues with the most abundant expression of Pold4. Moreover, Pold4 knockout mouse tail tip fibroblasts (TTF) exhibited normal cell growth, cell cycle, DNA replication, DNA damage and DNA repair capacity. These results suggested that Pol δ3 but not Pol δ4 may be responsible for these processes in normal cells. Interestingly, 19-month-old wild-type (WT) mice had tumors in the liver, while Pold4 knockout mice did not, and Pold4 knockout mice showed increased longevity. In further, this provided evidence suggested that Pold4 could be a potential novel target for lung carcinoma because its depletion does not affect normal cells but does affect cancer cells.
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Proteínas de Schizosaccharomyces pombe , Schizosaccharomyces , Camundongos , Animais , Replicação do DNA/genética , Reparo do DNA/genética , DNA Polimerase III/genética , Dano ao DNA , Ciclo Celular , Camundongos Knockout , Saccharomyces cerevisiae , MamíferosRESUMO
AIM: To report the clinical characteristics, treatment and outcomes of active syphilitic uveitis in human immunodeficiency virus (HIV) positive patients and compare them with the previously published data. METHODS: Retrospective analysis of the case series from an infectious disease center in southern China was conducted. Comprehensive review of previously published cases of HIV positive syphilitic uveitis was conducted using the PubMed and Web of Science databases and the references listed in the identified articles. RESULTS: Twelve HIV positive patients with active syphilitic uveitis were collected. All were male, with age of 36.3y (range 27 to 53y). Five (41.7%) had a history of syphilis, and three of them had received anti-syphilis treatment. Ocular manifestations included corneal epithelial defect (13%), complicated cataract (17.4%), vitreous opacity (82.6%), optic disc edema (26.1%), macular edema (30.4%), neuro-retinitis (43.5%), and retinal hemorrhage (26.1%). After standardized syphilitic treatment, intraocular inflammation was reduced and vision improved in all cases. The literature review summarizes 105 previously reported cases of HIV positive syphilitic uveitis. High serum rapid plasma regain (RPR) titers may be associated with severe uveitis and poor vision. Treatment with penicillin, ceftriaxone sodium, or penicillin plus benzylpenicillin instead of using benzylpenicillin alone can significantly improve best-corrected visual acuity (BCVA) in HIV positive ocular syphilis patients. CONCLUSION: For HIV positive syphilitic uveitis patients, prompt diagnosis and appropriate treatment and follow-up are paramount. In our series, the clinical manifestations are diverse. Syphilis patients treated by penicillin G or long-acting penicillin before may still develop syphilitic uveitis. Patients who relapse after long-term penicillin treatment can still benefit from penicillin G.
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Histone acetylation is one of the most common epigenetic modifications, which plays an important role in tumorigenesis. However, the prognostic role of histone acetylation-regulators in ovarian cancer (OC) remains little known. We compared the expression levels of 40 histone acetylation-related genes between 379 OC samples and 88 normal ovarian tissues and identified 37 differently expressed genes (DEGs). We further explored the prognostic roles of these DEGs, and 8 genes were found to be correlated with overall survival (p < 0.1). In the training stage, an 8 gene-based signature was conducted by the least absolute shrinkage and selector operator (LASSO) Cox regression. Patients in the training cohort were divided into two risk subgroups according to the risk score calculated by the 8-gene signature, and a notable difference of OS was found between the two subgroups (p < 0.001). The 8-gene risk model was then verified to have a well predictive role on OS in the external validation cohort. Combined with the clinical characteristics, the risk score was proved to be an independent risk factor for OS. In conclusion, the histone acetylation-based gene signature has a well predictive effect on the prognosis of OC and can potentially be applied for clinical treatments.
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Histone methylation is an epigenetic modification regulated by histone methyltransferases, histone demethylases, and histone methylation reader proteins that play important roles in the pathogenic mechanism of cancers. However, the prognostic value of histone methylation in lung adenocarcinoma (LUAD) remains unknown. Here, we found that LUAD cases could be divided into 2 subtypes by the 144 histone methylation modification regulators (HMMRs), with a significant difference in OS time. Ninety-five of the HMMRs were identified as differentially expressed genes (DEGs) between normal and tumor samples, and 13 of them were further discovered to be survival-related genes (SRGs). By applying the least absolute shrinkage and selector operator (LASSO) Cox regression, we constructed an 8-gene-based risk signature according to the TCGA (training) cohort, and the risk score calculated by the signature was proven to be an independent factor in both the training and validation cohorts. We then discovered that the immune functions were generally impaired in the high-risk groups defined by the HMMR signature (especially for the DCs and immune check-point pathway). Functional analyses showed that the DEGs between the low- and high-risk groups were related to the cell cycle. The drug sensitivity analysis indicated that our risk model could predict the sensitivity of commonly used drugs. Moreover, according to the DEGs between the low- and high-risk groups, we discovered several new compounds that showed potential therapeutic value for high-risk LUAD patients. In conclusion, our study demonstrated that HMMRs were promising predictors for the prognoses and drug therapeutic effects for LUAD patients.
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Multiple-band degeneracy has been widely recognized to be beneficial for high thermoelectric performance. Here, we discover that the p-type Dirac bands with lower degeneracy synergistically produce a higher Seebeck coefficient and electrical conductivity in topological semimetal BaAgBi. The anomalous transport phenomenon intrinsically originated from the asymmetric electronic structures: (i) complete p-type Dirac bands near the Fermi level facilitate high and strong energy-dependent hole relaxation time; (ii) the presence of additional parabolic conduction valleys allows for a large density of states to accept scattered electrons, leading to an enlarged hole-electron relaxation time ratio and, thus, weakened bipolar effect. In combination with the strong lattice anharmonicity, an exceptional p-type average ZT of 0.42 is achieved from 300 to 600 K, which can be dramatically enhanced to 1.38 via breaking the C3v symmetry. This work uncovers the underlying mechanisms governing the abnormal transport behavior in Dirac semimetal BaAgBi and highlights the asymmetric electronic structures as target features to discover/design high-performance thermoelectric materials.
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The SARS-CoV-2 Omicron BA.1 variant of concern contains more than 30 mutations in the spike protein, with half of these mutations localized in the receptor-binding domain (RBD). Emerging evidence suggests that these large number of mutations impact the neutralizing efficacy of vaccines and monoclonal antibodies. We investigated the relative contributions of spike protein and RBD mutations in Omicron BA.1 variants on infectivity, cell-cell fusion, and their sensitivity to neutralization by monoclonal antibodies or vaccinated sera from individuals who received homologous (CoronaVac, SinoPharm) or heterologous (CoronaVac-BNT162b2, BioNTech) and nonhuman primates that received a recombinant RBD protein vaccine. Our data overall reveal that the mutations in the spike protein reduced infectivity and cell-cell fusion compared to the D614G variant. The impaired infectivity and cell-cell fusion were dependent on non-RBD mutations. We also find reduced sensitivity to neutralization by monoclonal antibodies and vaccinated sera. However, our results also show that nonhuman primates receiving a recombinant RBD protein vaccine show substantial neutralization activity. Our study sheds light on the molecular differences in neutralizing antibody escape by the Omicron BA.1 variant, and highlights the promise of recombinant RBD vaccines in neutralizing the threat posed by the Omicron BA.1 variant.
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Ovarian cancer (OC) is a highly malignant gynaecological tumour that has a very poor prognosis. Pyroptosis has been demonstrated in recent years to be an inflammatory form of programmed cell death. However, the expression of pyroptosis-related genes in OC and their correlations with prognosis remain unclear. In this study, we identified 31 pyroptosis regulators that were differentially expressed between OC and normal ovarian tissues. Based on these differentially expressed genes (DEGs), all OC cases could be divided into two subtypes. The prognostic value of each pyroptosis-related gene for survival was evaluated to construct a multigene signature using The Cancer Genome Atlas (TCGA) cohort. By applying the least absolute shrinkage and selection operator (LASSO) Cox regression method, a 7-gene signature was built and classified all OC patients in the TCGA cohort into a low- or high-risk group. OC patients in the low-risk group showed significantly higher survival possibilities than those in the high-risk group (P < 0.001). Utilizing the median risk score from the TCGA cohort, OC patients from a Gene Expression Omnibus (GEO) cohort were divided into two risk subgroups, and the low-risk group had increased overall survival (OS) time (P = 0.014). Combined with the clinical characteristics, the risk score was found to be an independent factor for predicting the OS of OC patients. Gene ontology (GO) and Kyoto Encylopedia of Genes and Genomes (KEGG) analyses indicated that immune-related genes were enriched and that the immune status was decreased in the high-risk group. In conclusion, pyroptosis-related genes play important roles in tumour immunity and can be used to predict the prognosis of OCs.
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Ferroptosis is an iron-dependent, regulated form of cell death, and the process is complex, consisting of a variety of metabolites and biological molecules. Ovarian cancer (OC) is a highly malignant gynecologic tumor with a poor survival rate. However, the predictive role of ferroptosis-related genes in ovarian cancer prognosis remains unknown. In this study, we demonstrated that the 57 ferroptosis-related genes were expressed differently between ovarian cancer and normal ovarian tissue, and based on these genes, all OC cases can be well divided into 2 subgroups by applying consensus clustering. We utilized the least absolute shrinkage and selection operator (LASSO) cox regression model to develop a multigene risk signature from the TCGA cohort and then validated it in an OC cohort from the GEO database. A 5-gene signature was built and reveals a favorable predictive efficacy in both TCGA and GEO cohort (P < 0.001 and P = 0.03). The GO and KEGG analysis revealed that the differentially expressed genes (DEGs) between the low- and high-risk subgroup divided by our risk model were associated with tumor immunity, and lower immune status in the high-risk group was discovered. In conclusion, ferroptosis-related genes are vital factors predicting the prognosis of OC and could be a novel potential treatment target.
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BACKGROUND: Hypertensive disorders were proved to be associated with the development of depression. But it is unclear if pregnancy-induced hypertensive diseases, especially preeclampsia (PE), will affect postpartum moods. We aimed to determine the incidence rate of postpartum depression (PPD) in PE patients and comprehensively evaluate the association between PPD and PE, including its severity and complications. METHODS: 425 participants including 130 PE mothers were enrolled in this retrospective cohort study. Each woman was asked to complete a questionnaire integrating the Edinburgh Postnatal Depression Scale (EPDS), the Leakage Index Questionnaire, and a pain scale questionnaire within 6 weeks after delivery. The EPDS cut-off score above 13 was recognized as screening positive for PPD. Data between groups were compared by bivariate analysis. RESULTS: PE mothers showed a direct tendency to PPD development. The positive screening for PPD in the PE group was significantly higher than that of the control group (30.77% vs. 14.58%). Based on the results of the regression model, women diagnosed with severe PE and fetal growth restriction were more inclined to develop PPD than normal ones (AOR: 2.759, 95% CI: 1.206-6.315 and AOR: 3.450, 95% CI: 1.596-7.458). It is also indicated that postpartum pain exacerbated the odds of PPD in PE patients (AOR: 1.509, 95% CI: 1.078-2.114). CONCLUSIONS: PE was an independent risk factor for PPD. Its severity and complications exacerbate the development of PPD. Doctors and society should pay more attention to PE patients after delivery against the development of PPD.
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Depressão Pós-Parto/complicações , Depressão Pós-Parto/epidemiologia , Pré-Eclâmpsia/epidemiologia , Adolescente , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Gravidez , Escalas de Graduação Psiquiátrica , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
To assess the impact of the key non-synonymous amino acid substitutions in the RBD of the spike protein of SARS-CoV-2 variant B.1.617.1 (dominant variant identified in the current India outbreak) on the infectivity and neutralization activities of the immune sera, L452R and E484Q (L452R-E484Q variant), pseudotyped virus was constructed (with the D614G background). The impact on binding with the neutralizing antibodies was also assessed with an ELISA assay. Pseudotyped virus carrying a L452R-E484Q variant showed a comparable infectivity compared with D614G. However, there was a significant reduction in the neutralization activity of the immune sera from non-human primates vaccinated with a recombinant receptor binding domain (RBD) protein, convalescent patients, and healthy vaccinees vaccinated with an mRNA vaccine. In addition, there was a reduction in binding of L452R-E484Q-D614G protein to the antibodies of the immune sera from vaccinated non-human primates. These results highlight the interplay between infectivity and other biologic factors involved in the natural evolution of SARS-CoV-2. Reduced neutralization activities against the L452R-E484Q variant will have an impact on health authority planning and implications for the vaccination strategy/new vaccine development.
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PURPOSE: A small molecular compound, aminooxy-acetic acid (AOA), has been shown to modulate experimental autoimmune encephalomyelitis (EAE). The current study was designed to investigate whether AOA has a similar effect on the development of experimental autoimmune uveitis (EAU) and to further explore underlying mechanisms of this drug. METHODS: EAU was induced in C57BL/6J mice by immunization with interphotoreceptor retinoid-binding protein peptide 651-670 (IRBP 651-670). AOA (500µg or 750µg) or vehicle was administered by intraperitoneal injection from day 10 to 14 after EAU induction. The severity was assessed by clinical and histological scores. The integrity of the blood retinal barrier was detected with Evans Blue. Frequencies of splenic Th1, Th17 and Foxp3+ Treg cells were examined by flow cytometry. The production of cytokines was tested by ELISA. The mRNA expression of IL-17, IFN-γ and IL-10 was detected by RT-PCR. The expression of p-Stat1 and NF-κB was detected by Western Blotting. RESULTS: AOA was found to markedly inhibit the severity of EAU, as determined by clinical and histopathological examinations. AOA can relieve the leakage of blood retinal barrier (BRB). Functional studies found a decreased frequency of Th1 and Th17 cells and an increased frequency of Treg cells in EAU mice as compared with controls. Further studies showed that AOA not only downregulated the production of the proinflammatory cytokines including IFN-γ and IL-17 but also upregulated the expression of an anti-inflammatory cytokine such as IL-10, which might be caused by inhibiting the expressions of p-Stat1 and NF-κB. CONCLUSION: This study shows that AOA inhibits the severity and development of EAU by modulating the balance between regulatory and pathogenic lymphocyte subsets.