c-FLIP facilitates ZIKV infection by mediating caspase-8/3-dependent apoptosis.

c-FLIP functions as a dual regulator of apoptosis and inflammation, yet its implications in Zika virus (ZIKV) infection remain partially understood, especially in the context of ZIKV-induced congenital Zika syndrome (CZS) where both apoptosis and inflammation play pivotal roles. Our findings demonstrate that c-FLIP promotes ZIKV infection in placental cells and myeloid-derived macrophages, involving inflammation and caspase-8/3-mediated apoptosis. Moreover, our observations reveal that c-FLIP augments ZIKV infection in multiple tissues, including blood cell, spleen, uterus, testis, and the brain of mice. Notably, the partial deficiency of c-FLIP provides protection to embryos against ZIKV-induced CZS, accompanied by a reduction in caspase-3-mediated apoptosis. Additionally, we have found a distinctive parental effect of c-FLIP influencing ZIKV replication in fetal heads. In summary, our study reveals the critical role of c-FLIP as a positive regulator in caspase-8/3-mediated apoptosis during ZIKV infection, significantly contributing to the development of CZS.

Dysbiosis of oropharyngeal microbiome and antibiotic resistance in hospitalized COVID-19 patients.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is ongoing and multiple studies have elucidated its pathogenesis, however, the related- microbiome imbalance caused by SARS-CoV-2 is still not clear. In this study, we have comprehensively compared the microbiome composition and associated function alterations in the oropharyngeal swabs of healthy controls and coronavirus disease 2019 (COVID-19) patients with moderate or severe symptoms by metatranscriptomic sequencing. We did observe a reduced microbiome alpha-diversity but significant enrichment of opportunistic microorganisms in patients with COVID-19 compared with healthy controls, and the microbial homeostasis was rebuilt following the recovery of COVID-19 patients. Correspondingly, less functional genes in multiple biological processes and weakened metabolic pathways such as carbohydrate metabolism, energy metabolism were also observed in COVID-19 patients. We only found higher relative abundance of limited genera such as Lachnoanaerobaculum between severe patients and moderate patients while no worthy-noting microbiome diversity and function alteration were observed. Finally, we noticed that the co-occurrence of antibiotic resistance and virulence was closely related to the microbiome alteration caused by SRAS-CoV-2. Overall, our findings demonstrate that microbial dysbiosis may enhance the pathogenesis of SARS-CoV-2 and the antibiotics treatment should be critically considered.

Concurrent fabry disease and immunoglobulin a nephropathy: a case report.

BACKGROUND: Fabry disease (FD) is an X-linked, hereditary dysfunction of glycosphingolipid storage caused by mutations in the GLA gene encoding alpha-galactosidase A enzyme. In rare cases, FD may coexist with immunoglobulin A nephropathy (IgAN). We describe a case of concurrent FD, IgAN, and dilated cardiomyopathy-causing mutations in the TTN and BAG3 genes, which has not been reported previously. CASE PRESENTATION: A 60-year-old female patient was admitted with a one-week history of facial and lower-limb edema, two-year history of left ventricular hypertrophy and sinus bradycardia, and recurring numbness and pain in three lateral digits with bilateral thenar muscle atrophy. Renal biopsy revealed concurrent FD (confirmed via an alpha-galactosidase A enzyme assay, Lyso-GL-3 quantification, and GLA gene sequencing) and IgAN. Heterozygous mutations in the TTN (c.30,484 C > A;p.P10162T) and BAG3 (c.88 A > G;p.I30V) genes were observed. The patient reported that two of her brothers had undergone kidney transplantation; one died suddenly at 60 years of age, and the other required a cardiac pacemaker. The 35-year-old son of the patient was screened for the GLA gene mutation and found to be positive for the same mutation as the patient. The patient was administered oral losartan (50 mg/day). Enzyme replacement therapy was refused due to financial reasons. Her renal and cardiac functions were stable yet worth closely monitoring during follow-up. CONCLUSION: The family history of patients with concurrent heart and renal diseases should be assessed in detail. Genetic testing and histological examinations are essential for diagnosing FD with IgAN.

ZIKV induces P62-mediated autophagic degradation of TRAF6 through TRAF6-NS1 interaction.

Tumor necrosis factor receptor-associated factor 6 (TRAF6) is crucial in flavivirus infections, modulating the host immune response through interactions with viral proteins. Despite its importance, the relationship between TRAF6 and Zika virus (ZIKV) remains poorly understood. Our prior proteomics analysis revealed reduced TRAF6 protein levels in ZIKV-infected human trophoblast cells compared to non-infected controls. Subsequent studies in cell models and murine tissues confirmed a significant reduction in both TRAF6 mRNA and protein levels post-ZIKV infection. Further investigations unveiled that ZIKV induces P62-mediated degradation of TRAF6, with NS1 identified as the primary contributor. Co-localization and interaction studies demonstrated that NS1 promotes the association of P62, a key autophagy mediator, with TRAF6. Notably, our findings revealed TRAF6 enhances ZIKV infection, NS1 ubiquitination, NS1 expression, and the production of inflammatory cytokines and chemokines. These insights highlight the intricate TRAF6-ZIKV relationship, offering potential for drug targeting NS1-TRAF6 interactions to manage ZIKV infections effectively.

A broad-spectrum multiepitope vaccine against seasonal influenza A and B viruses in mice.

BACKGROUND: Influenza viruses pose a persistent threat to global public health, necessitating the development of innovative and broadly effective vaccines. METHODS: This study focuses on a multiepitope vaccine (MEV) designed to provide broad-spectrum protection against different influenza viruses. The MEV, containing 19 B-cell linear epitopes, 7 CD4+ T cells, and 11 CD8+ T cells epitopes identified through enzyme-linked immunospot assay (ELISPOT) in influenza viruses infected mice, was administered through a regimen of two doses of DNA vaccine followed by one dose of a protein vaccine in C57BL/6 female mice. FINDINGS: Upon lethal challenge with both seasonal circulating strains (H1N1, H3N2, BV, and BY) and historical strains (H1N1-PR8 and H3N2-X31), MEV demonstrated substantial protection against different influenza seasonal strains, with partial efficacy against historical strains. Notably, the increased germinal centre B cells and antibody-secreting cells, along with robust T cell immune responses, highlighted the comprehensive immune defence elicited by MEV. Elevated hemagglutinin inhibition antibody was also observed against seasonal circulating and historical strains. Additionally, mice vaccinated with MEV exhibited significantly lower counts of inflammatory cells in the lungs compared to negative control groups. INTERPRETATION: Our results demonstrated the efficacy of a broad-spectrum MEV against influenza viruses in mice. Conducting long-term studies to evaluate the durability of MEV-induced immune responses and explore its potential application in diverse populations will offer valuable insights for the continued advancement of this promising vaccine. FUNDING: Funding bodies are described in the Acknowledgments section.

ZIKV infection differentially affects the transcriptional profiles in HTR8 and U251 cells.

The mechanism by which Zika virus (ZIKV) causes severe birth defects in pregnant women remains unclear. Cell tropisms in placenta and brain play a crucial role in ZIKV pathogenesis, leading to congenital Zika syndrome (CZS). To identify the host factors involved in ZIKV infection, we compared the transcriptional profiles of ZIKV-infected human first-trimester placental trophoblast cells HTR8/SVneo and a human glioblastoma astrocytoma cell line U251. Our results demonstrated that ZIKV exhibited lower rates of mRNA replication and protein expression in HTR8 than in U251 cells, while showing a higher release of infectious viral particles. However, a greater number of differentially expressed genes (DEGs) were found in ZIKV-infected U251 cells than in ZIKV-infected HTR8 cells. Several of these DEGs were enriched in distinct biological processes related to the characteristics of each cell type that may contribute to foetal damage. Both cell types exhibited activation of common interferons, inflammatory cytokines, and chemokine production upon ZIKV infection. Moreover, the neutralization of tumour necrosis factor-alpha (TNF-α) promoted ZIKV infection in both trophoblasts and glioblastoma astrocytoma cells. Overall, we identified multiple DEGs associated with ZIKV pathogenesis.

Molecular and Clinical Characterization of CD80 Expression via Large-Scale Analysis in Breast Cancer.

Cancer immunotherapy is emerging as a novel promising therapy option for cancer patients. Despite the critical role of CD80 in the regulation of immune responses, the expression and biological functions of CD80 in breast cancer remain unknown. In this study, we aimed to investigate the role of CD80 both clinically and molecularly in breast cancer at a transcriptome level. Herein, we first analyzed the transcriptome profile and relevant clinical information derived from a total of 1090 breast cancer patients recorded in The Cancer Genome Atlas database and then validated this in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) database (n = 1904). We revealed the associations of CD80 and the main molecular and clinical characteristics of breast cancer. The gene ontology analysis and Gene Set Variation Analysis of the CD80-related genes revealed that CD80 was closely correlated with immune responses and inflammatory activities in breast cancer. Moreover, the CD80 expression showed a remarkable positive correlation with several infiltrated immune cell populations. In summary, the CD80 expression was closely correlated with the malignancy of breast cancer, and our findings suggest that CD80 might be a promising target for immunotherapeutic strategies. To the best of our knowledge, this is the first integrative study characterizing the role of the CD80 expression in breast cancer via large-scale analyses.

Pre-existing humoral immunity to low pathogenic human coronaviruses exhibits limited cross-reactive antibodies response against SARS-CoV-2 in children.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes asymptomatic or mild symptoms, even rare hospitalization in children. A major concern is whether the pre-existing antibodies induced by low pathogenic human coronaviruses (LPH-CoVs) in children can cross-react with SARS-CoV-2. To address this unresolved question, we analyzed the pre-existing spike (S)-specific immunoglobin (Ig) G antibodies against LPH-CoVs and the cross-reactive antibodies against SARS-CoV-2 in 658 serum samples collected from children prior to SARS-CoV-2 outbreak. We found that the seroprevalence of these four LPH-CoVs reached 75.84%, and about 24.64% of the seropositive samples had cross-reactive IgG antibodies against the nucleocapsid, S, and receptor binding domain antigens of SARS-CoV-2. Additionally, the re-infections with different LPH-CoVs occurred frequently in children and tended to increase the cross-reactive antibodies against SARS-CoV-2. From the forty-nine serum samples with cross-reactive anti-S IgG antibodies against SARS-CoV-2, we found that seven samples with a median age of 1.4 years old had detected neutralizing activity for the wild-type or mutant SARS-CoV-2 S pseudotypes. Interestingly, all of the seven samples contained anti-S IgG antibodies against HCoV-OC43. Together, these data suggest that children's pre-existing antibodies to LPH-CoVs have limited cross-reactive neutralizing antibodies against SRAS-CoV-2.

Renal failure and hepatitis following ingestion of raw grass carp gallbladder: A case report.

BACKGROUND: Fish gallbladder has long been used as a folk remedy in Asian countries. Multiple organ damage after ingestion of fish gallbladder resulting in near mortality has been known to us. Here, we describe a case of acute renal failure (ARF) and hepatitis due to grass carp gallbladder poisoning and review the literature. CASE SUMMARY: A previously healthy, 50-year-old woman was admitted to our hospital with a 2-d history of generalized abdominal pain and repeated vomiting following ingestion of two raw grass carp gallbladders in an attempt to alleviate her cough. She developed anuria on day 4 with markedly elevated serum creatinine, urea, bilirubin, alanine aminotransferase, and aspartate aminotransferase. Based on thorough evaluation of her history and prompt biochemical investigations, we diagnosed her with ARF and hepatitis secondary to fish gallbladder poisoning. Her renal biopsy revealed acute tubular necrosis, following which she underwent six sessions of conventional hemodialysis due to renal failure. Supportive treatment with gastric mucosal protectant and liver protectant was administered for targeted organ protection. The patient's liver function gradually recovered, and serum creatinine was 164 mmol/L at discharge on day 24. Over a follow-up period of 2 wk, her renal function completely recovered. CONCLUSION: Physicians should be mindful of toxic complications of raw grass carp gallbladder ingestion and we should promote awareness to reduce incidences of food poisoning.

Establishing a prediction model of axillary nodal burden based on the combination of CT and ultrasound findings and the clinicopathological features in patients with early-stage breast cancer.

BACKGROUND: Axillary lymph node (ALN) management in early-stage breast cancer (ESBC) patients has become less invasive during the past decades. Here, we tried to explore whether high nodal burden (HNB) in ESBC patients could be predicted preoperatively, so as to avoid unnecessary sentinel lymph node biopsy (SLNB). METHODS: The clinicopathological and imaging data of patients with early invasive breast cancer (cT1-2N0M0) were analyzed retrospectively. Univariate and multivariate analyses were performed for the risk factors of axillary HNB in ESBC patients, and a risk prediction model of HNB was established. RESULTS: HNB was identified in 105 (8.0%) of 1,300 ESBC patients. Multivariate analysis showed that estrogen receptors (ER) status, human epidermal growth factor receptor 2 (HER2) status, number of abnormal lymph nodes (LNs) on computed tomography (CT), and axillary score on ultrasound (US) were the risk factors of HNB (all P<0.05). The area under the receiver operating characteristic (ROC) curve in the prediction model was 0.914, with the sensitivity being 85.7% and the specificity being 82.4%. The calibration curve showed that the prediction model had good performance. CONCLUSIONS: As a valuable tool for predicting HNB in ESBC patients, this newly established model helps clinicians to make reasonable axillary surgery decisions and thus avoid unnecessary SLNB.

Differential effects of three amendments on the immobilisation of cadmium and lead for Triticum aestivum grown on polluted soil.

Conventional chemical soil amendments and novel material biochars have been widely reported for the immobilisation of cadmium (Cd) and lead (Pb) in polluted soil. However, information regarding their comparative effectiveness is poor. In the present study, rice husk biochar (RHB) was compared with two chemical soil amendments including hydroxyapatite (HAP) and hydrated lime (HDL) for their effectiveness to enhance plant growth and the reduction of Cd uptake and translocation by Triticum aestivum L. grown in heavy-metal-polluted soil. Compared with control and two chemical soil amendments, RHB rapidly improved wheat growth. The HAP, HDL, and RHB treated plants retained Cd and Pb in roots and restricted their translocation. The RHB treatment had the best effect on growth, yield promotion and the reduction of Cd and Pb in wheat grain. Furthermore, the soils treated with RHB and HAP showed lower DTPA-extracted Cd concentrations, and the maximum reduction was observed in HAP-amended soil. However, the DTPA-extracted Pb concentration was not significantly decreased after the application of two chemical soil amendments for 40 days; the maximum reduction was found in soil treated with RHB for 80 days. In all treatments, Cd in post-harvest soil was mainly present in exchangeable, carbonate bound, and Fe-Mn oxide Cd, while the dominant chemical form of Pb was Fe-Mn oxide Pb. Three soil amendments application decreased exchangeable and organic bound- Cd and Pb levels. HAP and RHB displayed significantly immobilisation for soil Cd and reduced translocation of heavy metal as well as its availability in soil, but the HAP had significant inhibition on growth of wheat in contaminated soil. Therefore, RHB shows a promising potential for the reduction of Cd and Pb bioaccumulation in grains from wheat grown on heavy-metal-polluted soils.

Long non-coding RNA LINC00968 reduces cell proliferation and migration and angiogenesis in breast cancer through up-regulation of PROX1 by reducing hsa-miR-423-5p.

Background: Breast cancer (BC) is a common invasive malignancy in women with unclear etiology. A recent study suggested that long non-coding RNA (lncRNA), LINC00968 had a tumor-promoting effect in cancer. However, the role of LINC00968 in BC remains unclear. Therefore, we conducted the present study to determine the effect of LINC00968 in BC and its underlying mechanism. Methods: The expression of LINC00968 and hsa-miR-423-5p in BC tissues and cells was determined using reverse transcription quantitative polymerase chain reaction and western blot analysis. Dual luciferase reporter, RNA pull-down and RNA immunoprecipitation assays were used to determine the relationship among LINC00968, PROX1 and hsa-miR-423-5p. Gain- and loss-function approaches were utilized to examine the effects of LINC00968, PROX1 and hsa-miR-423-5p on cell proliferation, migration, tube formation in vitro; and tumor growth and angiogenesis in vivo. Results: LINC00968 expression reduced while hsa-miR-423-5p increased in BC tissues relative to adjacent normal tissues. Overexpression of LINC00968 was observed to inhibit BC cell proliferation, migration and tube formation abilities in vitro as well as tumor growth in vivo through inhibition of hsa-miR-423-5p. And hsa-miR-423-5p mediated BC cellular functions and tumor growth through down-regulating PROX1. LINC00968 was identified as a competing endogenous RNA to upregulate PROX1 by downregulating hsa-miR-423-5p. More importantly, it was found that LINC00968 increased PROX1 expression in vivo in a concentration-dependent manner. Conclusion: Taken together, this study suggests that LINC00968 inhibits the progression of BC through impeding hsa-miR-423-5p-mediated PROX1 inhibition. LINC00968 may be a potential therapeutic target for BC therapy that warrants further studies.