Antibodies against the receptor-binding-domain of the SARS-CoV-2 spike protein prevent SARS-CoV-2 infection. However, the effects of antibodies against other spike protein domains are largely unknown. Here, we screened a series of anti-spike monoclonal antibodies from COVID-19 patients, and found that some of antibodies against the N-terminal-domain (NTD) induced the open conformation of receptor binding domain (RBD) and thus enhanced the binding capacity of the spike protein to ACE2 and infectivity of SARS-CoV-2. Mutational analysis revealed that all the infectivity-enhancing antibodies recognized a specific site on the NTD. Structural analysis demonstrated that all the infectivity-enhancing antibodies bound to NTD in a similar manner. The antibodies against this infectivity-enhancing site were detected at high levels in severe patients. Moreover, we identified antibodies against the infectivity-enhancing site in uninfected donors, albeit at a lower frequency. These findings demonstrate that not only neutralizing antibodies but also enhancing antibodies are produced during SARS-CoV-2 infection.

The background frequency of t(14;18) (q32;q21) chromosomal tranlocations at the locus associated with B-cell leukemia/lymphoma-2 (BCL2) was determined from a survey ofthe peripheral blood lymphocytes (PBLs) of53 living Individuals and from tissues of 31 autopsies by using a nested PCR assay. The translocation was detected in 55% of It has been thought that most human tumor clones arise from a single transformed cell and that tumor progression is a multistep process requiring multiple mutational hits at oncogenes and tumor-suppressor genes (1-6). Since multiple hits at oncogenic loci are thought to be required for tumorigenesis, one might expect oncogenic mutations to occur in humans who have not yet developed tumors, given sufficiently sensitive techniques (7). The incidence of most tumors rises strikingly with age (8), and if mutational hits at oncogenic loci are a prerequisite for tumorigenesis, one might then expect the frequency of somatic mutations at oncogenic loci to rise with age. Although such expectations have existed for many years and evidence has accumulated that rare mutational hits accumulate at nononcogenic loci with age (9, 10), an age-related increase in mutations at an oncogenic locus has not been shown.Non-Hodgkin lymphoma (NHL) is a tumor of B-lymphocyte origin, whose incidence rises more than 40-fold with human age (11). As in many other hematological neoplasms (12)(13)(14), specific chromosomal translocations occur in the two types of NHL, follicular lymphoma and diffuse B-cell lymphoma (15). The t(14;18)(q32;q21) translocation occurs in 85% of follicular lymphomas and 20% of diffuse B-cell lymphomas (11). Such translocations juxtapose the BCL2 (B-cell leukemia/lymphoma-2) locus on chromosome 18 with the immunoglobulin heavy chain joining (J) region gene on chromosome 14, resulting in dysregulated expression of the BCL2 gene (16,17). Dysregulated expression of this locus prolongs the survival of B cells, by delaying programmed cell death (18,19).We have developed a nested PCR assay for quantitation of rare t(14;18) translocations to test the hypotheses that such oncogenic mutations may occur (i) in persons without lymphoid neoplasia and (ii) in an age-dependent fashion. MATERIALS AND METHODSPreparation of DNA. Fifty-three blood samples from live persons and tissues from 31 autopsies were collected at the Los Angeles County Hospital, CA. Blood samples were kept at 40C no more than 72 hr prior to lymphocyte separation. PBLs were prepared as described by Boyum (20) and were frozen at -200C until DNA extraction. Autopsy tissues were maintained at -800C prior to DNA preparation and then minced with a razor blade, and DNA was extracted by standard methods (21). All autopsy DNA samples were tested for degradation by a control PCR amplification with primers PA1 and Pc (5'-AAG GTC TGA TCA TTC TGTTCC) (Fig. 1); samples that yielded a PCR signal when amplified for 30 cycles were used. Two spleen DNA samples were found degraded by this test and were excluded.To generate B cell-enriched and -d...

Fecal microbiota transplantation (FMT) by manual preparation has been applied to treat diseases for thousands of years. However, this method still endures safety risks and challenges the psychological endurance and acceptance of doctors, patients and donors. Population evidence showed the washed microbiota preparation with microfiltration based on an automatic purification system followed by repeated centrifugation plus suspension for three times significantly reduced FMT-related adverse events. This washing preparation makes delivering a precise dose of the enriched microbiota feasible, instead of using the weight of stool. Intraperitoneal injection in mice with the fecal microbiota supernatant obtained after repeated centrifugation plus suspension for three times induced less toxic reaction than that by the first centrifugation following the microfiltration. The toxic reactions that include death, the change in the level of peripheral white blood cells, and the proliferation of germinal center in secondary lymphoid follicles in spleen were noted. The metagenomic next-generation sequencing (NGS) indicated the increasing types and amount of viruses could be washed out during the washing process. Metabolomics analysis indicated metabolites with pro-inflammatory effects in the fecal microbiota supernatant such as leukotriene B4, corticosterone, and prostaglandin G2 could be removed by repeated washing. Near-infrared absorption spectroscopy could be served as a rapid detection method to control the quality of the washingprocess. In conclusion, this study for the first time provides evidence linking clinical findings and animal experiments to support that washed microbiota transplantation (WMT) is safer, more precise and more quality-controllable than the crude FMT by manual.

Human ingestion of microplastics (MPs) is inevitable due to the ubiquity of MPs in various foods and drinking water. Whether the ingestion of MPs poses a substantial risk to human health is far from understood. Here, by analyzing the characteristics of MPs in the feces of patients with inflammatory bowel disease (IBD) and healthy people, for the first time, we found that the fecal MP concentration in IBD patients (41.8 items/g dm) was significantly higher than that in healthy people (28.0 items/g dm). In total, 15 types of MPs were detected in feces, with poly­(ethylene terephthalate) (22.3–34.0%) and polyamide (8.9–12.4%) being dominant, and their primary shapes were sheets and fibers, respectively. We present evidence indicating that a positive correlation exists between the concentration of fecal MPs and the severity of IBD. Combining a questionnaire survey and the characteristics of fecal MPs, we conclude that the plastic packaging of drinking water and food and dust exposure are important sources of human exposure to MPs. Furthermore, the positive correlation between fecal MPs and IBD status suggests that MP exposure may be related to the disease process or that IBD exacerbates the retention of MPs. The relative mechanisms deserve further studies. Our results also highlight that fecal MPs are useful for assessing human MP exposure and potential health risks.

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Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. The incidence of HCC is strikingly higher in males than in females. The remarkable gender disparity suggests an important role for sex hormones in HCC pathogenesis. Recently, estrogen has emerged as a protective factor in the development and progression of HCC, but whether it prevents and attenuates HCC, and the mechanism of protection, have not been elucidated. The present study shows that expression of estrogen receptor (ER) β was significantly downregulated in HCC tissue compared with normal liver tissue; moreover, its expression level showed a significant negative correlation with disease progression and a positive correlation with the expression level of NLRP3 inflammasome components. In a previous study, we showed that loss of NLRP3 inflammasome in HCC tissue contributed to tumor progression, whereas the mechanism of its deregulation was not elucidated. In this study, we investigated the potential link between NLRP3 inflammasome and estrogen. Our data reveal that treatment with 17β-estradiol (E2) significantly inhibited the malignant behavior of HCC cells through E2/ERβ/ MAPK pathway-mediated upregulation of the NLRP3 inflammasome. This study shows a novel link between ERβ and the NLRP3 inflammasome in HCC progression, which provides a potentially valuable therapeutic strategy for treatment of HCC patients.

No abstract

The widespread occurrence of SARS-CoV-2 has had a profound effect on society and a vaccine is currently being developed. Angiotensin-converting enzyme 2 (ACE2) is the primary host cell receptor that interacts with the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. Although pneumonia is the main symptom in severe cases of SARS-CoV-2 infection, the expression levels of ACE2 in the lung is low, suggesting the presence of another receptor for the spike protein. In order to identify the additional receptors for the spike protein, we screened a receptor for the SARS-CoV-2 spike protein from the lung cDNA library. We cloned L-SIGN as a specific receptor for the N-terminal domain (NTD) of the SARS-CoV-2 spike protein. The RBD of the spike protein did not bind to L-SIGN. In addition, not only L-SIGN but also DC-SIGN, a closely related C-type lectin receptor to L-SIGN, bound to the NTD of the SARS-CoV-2 spike protein. Importantly, cells expressing L-SIGN and DC-SIGN were both infected by SARS-CoV-2. Furthermore, L-SIGN and DC-SIGN induced membrane fusion by associating with the SARS-CoV-2 spike protein. Serum antibodies from infected patients and a patient-derived monoclonal antibody against NTD inhibited SARS-CoV-2 infection of L-SIGN or DC-SIGN expressing cells. Our results highlight the important role of NTD in SARS-CoV-2 dissemination through L-SIGN and DC-SIGN and the significance of having anti-NTD neutralizing antibodies in antibody-based therapeutics.