Prophylactic efficacy of an intranasal spray with 2 synergetic antibodies neutralizing Omicron.

BACKGROUNDAs Omicron is prompted to replicate in the upper airway, neutralizing antibodies (NAbs) delivered through inhalation might inhibit early-stage infection in the respiratory tract. Thus, elucidating the prophylactic efficacy of NAbs via nasal spray addresses an important clinical need.METHODSThe applicable potential of a nasal spray cocktail containing 2 NAbs was characterized by testing its neutralizing potency, synergetic neutralizing mechanism, emergency protective and therapeutic efficacy in a hamster model, and pharmacokinetics/pharmacodynamic (PK/PD) in human nasal cavity.RESULTSThe 2 NAbs displayed broad neutralizing efficacy against Omicron, and they could structurally compensate each other in blocking the Spike-ACE2 interaction. When administrated through the intranasal mucosal route, this cocktail demonstrated profound efficacy in the emergency prevention in hamsters challenged with authentic Omicron BA.1. The investigator-initiated trial in healthy volunteers confirmed the safety and the PK/PD of the NAb cocktail delivered via nasal spray. Nasal samples from the participants receiving 4 administrations over a course of 16 hours demonstrated potent neutralization against Omicron BA.5 in an ex vivo pseudovirus neutralization assay.CONCLUSIONThese results demonstrate that the NAb cocktail nasal spray provides a good basis for clinical prophylactic efficacy against Omicron infections.TRIAL REGISTRATIONwww.chictr.org.cn, ChiCTR2200066525.FUNDINGThe National Science and Technology Major Project (2017ZX10202203), the National Key Research and Development Program of China (2018YFA0507100), Guangzhou National Laboratory (SRPG22-015), Lingang Laboratory (LG202101-01-07), Science and Technology Commission of Shanghai Municipality (YDZX20213100001556), and the Emergency Project from the Science & Technology Commission of Chongqing (cstc2021jscx-fyzxX0001).

A novel four­gene biomarker for tobacco smoking -induced colorectal cancer progression.

INTRODUCTION: Cigarette smoking greatly promotes the progression and poor prognosis of colorectal cancer (CRC) patients, with the molecular mechanism still not fully clear. METHODS: In this study, CRC cells were exposed to tobacco specific nitrosamine 4­(methylnitrosamino)­1­(3­pyridyl) 1­butanone (NNK), and the differentially expressed smoking-related genes were identified based on both NNK-induced CRC cells and a total of 763 CRC tissues from TCGA cohort. Cox regression analysis, ROC curve and Kaplan-Meier plot were used to establish the risk score model for CRC prognosis. Moreover, qRT-PCR, western blotting, colony formation, migration and invasion assays were performed to verify the core differentially expressed smoking-related gene and its molecular function in NNK-induced CRC progression. RESULTS: Results indicated NNK significantly enhanced CRC cell proliferation, migration and invasion. Moreover, a four-gene signature containing AKR1B10, CALB2, PLAC1, GNA15 was established as CRC prognosis marker. Among these four genes, AKR1B10 was further validated as the core gene, and its expression was significantly inhibited after NNK exposure in CRC cells. Results of gene enrichment analysis and western blotting suggested AKR1B10 might reduce the malignant progression of NNK-induced CRC cells through inhibiting Wnt signaling pathway by promoting E-Cadherin expression and inhibiting the expression of N-Cadherin, ß-Catenin, Vimentin and Snail. CONCLUSION: In conclusion, a new four smoking-related genes can be jointly used as prognostic markers for CRC. AKR1B10 served as a tumor suppressor, can be used as a potential target to inhibit NNK-induced CRC malignant progression through regulating Wnt signaling pathway. IMPLICATIONS: This study demonstrates tobacco-derived NNK dependence would promote the malignant progression of colorectal cancer through regulating the expressions of AKR1B10/Wnt signaling pathway. And a novel four-gene signature is established for the prognosis prediction of smoking CRC patients. These findings have important translational implications given the continued use of tobacco and the difficulty in smoking cessation worldwide, which can be applied to alleviate the adverse effects induced by tobacco dependence on colorectal cancer patients.

Potent human neutralizing antibodies against Nipah virus derived from two ancestral antibody heavy chains.

Nipah virus (NiV) is a World Health Organization priority pathogen and there are currently no approved drugs for clinical immunotherapy. Through the use of a naïve human phage-displayed Fab library, two neutralizing antibodies (NiV41 and NiV42) targeting the NiV receptor binding protein (RBP) were identified. Following affinity maturation, antibodies derived from NiV41 display cross-reactivity against both NiV and Hendra virus (HeV), whereas the antibody based on NiV42 is only specific to NiV. Results of immunogenetic analysis reveal a correlation between the maturation of antibodies and their antiviral activity. In vivo testing of NiV41 and its mature form (41-6) show protective efficacy against a lethal NiV challenge in hamsters. Furthermore, a 2.88 Å Cryo-EM structure of the tetrameric RBP and antibody complex demonstrates that 41-6 blocks the receptor binding interface. These findings can be beneficial for the development of antiviral drugs and the design of vaccines with broad spectrum against henipaviruses.

A potential bivalent mRNA vaccine candidate protects against both RSV and SARS-CoV-2 infections.

As the world continues to confront severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), respiratory syncytial virus (RSV) is also causing severe respiratory illness in millions of infants, elderly individuals, and immunocompromised people globally. Exacerbating the situation is the fact that co-infection with multiple viruses is occurring, something which has greatly increased the clinical severity of the infections. Thus, our team developed a bivalent vaccine that delivered mRNAs encoding SARS-CoV-2 Omicron spike (S) and RSV fusion (F) proteins simultaneously, SF-LNP, which induced S and F protein-specific binding antibodies and cellular immune responses in BALB/c mice. Moreover, SF-LNP immunization effectively protected BALB/c mice from RSV infection and hamsters from SARS-CoV-2 Omicron infection. Notably, our study pointed out the antigenic competition problem of bivalent vaccines and provided a solution. Overall, our results demonstrated the potential of preventing two infectious diseases with a single vaccine and provided a paradigm for the subsequent design of multivalent vaccines.

Long-term immune response to Omicron-specific mRNA vaccination in mice, hamsters, and nonhuman primates.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron and its subvariants (such as BQ.1, XBB and the latest variants, including XBB.1.16, EG.5, and BA.2.86), as the dominant variants, currently account for almost all new infections in the world due to their high transmissibility and immune escape ability. Omicron-specific mRNA vaccines showed great potential to protect against Omicron infections. However, whether the vaccine could provide long-term protection is unknown. Toward this goal, we evaluated the immunogenicity of a preclinical Omicron (BA.1)-specific mRNA vaccine (SOmicron-6P) in different animal models. SOmicron-6P induced the highest levels of antibody titers at 1-2 weeks in different animals after the second dose. Even 9 months after the immunization, we observed modest neutralizing activity against Omicron subvariants in macaques. In addition, immunological memory cells can be rapidly reactivated upon stimulation. SOmicron-6P at concentrations higher than 10 µg effectively protected hamsters from BA.1 challenge 253 days after the first immunization, which could be attributed to the reactivation of immune systems. In addition, the toxicity tests conducted in rats revealed a highly favorable biosafety profile for SOmicron-6P, even at high dosages. Our data suggest that the Omicron-specific mRNA vaccine is highly effective and safe in animal models and provides long-term immunologic protection against SARS-CoV-2 Omicron infections.

Identification of Key Novel lncRNAs RP11-400N13.3 and RP11-197K6.1 that Construct ceRNA Networks Associated with Recurrence and Metastasis in Colon Cancer.

BACKGROUND: Colon adenocarcinoma (COAD) is a major cause of cancer mortality worldwide. The occurrence and development of colon cancer is regulated by complex mechanisms that require further exploration. Recently, long non-coding RNAs (lncRNAs) were found to be related to the mortality of colon cancer patients through their participation in competing endogenous RNA (ceRNA) networks. Therefore, screening the lncRNAs involved in colon cancer may contribute to clarifying the complex mechanisms. METHODS: In this study, we explored the potential lncRNAs associated with colon cancer by establishing a ceRNA network using bioinformatics, followed by biological verification. RESULTS: RP11-197K6.1 and RP11-400N13.3 were screened out owing to their involvement in the expression of CDK2NA, a gene that potentially prevents colon cancer cells from high oxygen levels. CONCLUSIONS: Our work explored the mechanisms of recurrence and metastasis in colon cancer and provided potential targets for drug development.

An engineered bispecific nanobody in tetrameric secretory IgA format confers broad neutralization against SARS-CoV-1&2 and most variants.

SARS-CoV-2, a type of respiratory virus, has exerted a great impact on global health and economy over the past three years. Antibody-based therapy was initially successful but later failed due to the accumulation of mutations in the spike protein of the virus. Strategies that enable antibodies to resist virus escape are therefore of great significance. Here, we engineer a bispecific SARS-CoV-2 neutralizing nanobody in secretory Immunoglobulin A (SIgA) format, named S2-3-IgA2m2, which shows broad and potent neutralization against SARS-CoV-1, SARS-CoV-2 and its variants of concern (VOCs) including XBB and BQ.1.1. S2-3-IgA2m2 is ∼1800-fold more potent than its parental IgG counterpart in neutralizing XBB. S2-3-IgA2m2 is stable in mouse lungs at least for three days when administrated by nasal delivery. In hamsters infected with BA.5, three intranasal doses of S2-3-IgA2m2 at 1 mg/kg significantly reduce viral RNA loads and completely eliminate infectious particles in the trachea and lungs. Notably, even at single dose of 1 mg/kg, S2-3-IgA2m2 prophylactically administered through the intranasal route drastically reduces airway viral RNA loads and infectious particles. This study provides an effective weapon combating SARS-CoV-2, proposes a new strategy overcoming the virus escape, and lays strategic reserves for rapid response to potential future outbreaks of "SARS-CoV-3".

KED gene expression in early response to wounding stress in tomato plants.

The wounding-responsive KED gene, named for its coding for a lysine (K), glutamic acid (E), and aspartic acid (D)-rich protein, is widely present among land plants. However, little is known about its regulation or function. In this study, we found that transcription of the tomato (Solanum lycopersicum) KED gene, SlKED, was rapidly and transiently elevated by wounding or ethephon treatment. Compared to the wild-type plants, the CRISPR/Cas9-mediated SlKED knockout plants did not exhibit altered expression patterns for genes involved in hormone biosynthesis or stress signaling, suggesting a lack of pleiotropic effect on other stress-responsive genes. Conversely, jasmonic acid did not appear to directly regulate SlKED expression. Wounded leaves of the KED-lacking plants exhibited higher binding of Evans blue dye than the wild-type, indicating a possible role for KED in healing damaged tissues. The SlKED knockout plants showed a similar dietary effect as the wild-type on the larval growth of tobacco hornworm. But a higher frequency of larval mandible (mouth) movement was recorded during the first 2 minutes of feeding on the wounded KED-lacking SlKED knockout plants than on the wounded KED-producing wild-type plants, probably reflecting an initial differential response by the feeding larvae to the SlKED knockout plants. Our findings suggest that SlKED may be an ethylene-mediated early responder to mechanical stress in tomato, acting downstream of the wound stress response pathways. Although its possible involvement in response to other biotic and abiotic stresses is still unclear, we propose that SlKED may play a role in plant's rapid, short-term, early wounding responses, such as in cellular damage healing.

Purple Yam Polyphenol Extracts Exert Anticolitis and Anticolitis-Associated Colorectal Cancer Effects through Inactivation of NF-κB/p65 and STAT3 Signaling Pathways.

Colorectal cancer is a malignancy with high incidence and mortality worldwide, and ulcerative colitis (UC) is strongly associated with colorectal cancer. Purple yam, also known as Dioscorea alata, has been reported to be rich in plant polyphenols that have possessed anti-inflammatory, antioxidant, and antitumor properties. However, it is not clear whether purple yam polyphenol extracts (PYPE) can improve colitis and inhibit colitis-related colorectal tumorigenesis. Therefore, we used dextran sulfate sodium (DSS)-induced colitis and azoxymethane (AOM)/DSS-induced colitis-associated colorectal cancer (CAC) models in mice to evaluate the preventive value and possible mechanisms of PYPE. It was found that PYPE effectively alleviated DSS-induced colitis, inhibited macrophage infiltration, and reduced the production of the pro-inflammatory cytokines, such as TNF-α, IL-6, IL-1ß, IL-17A, CXCL1, and MCP-1, and the higher the concentration of PYPE, the better the inhibitory effect. In addition, PYPE dramatically prevented the development of CAC and tumor proliferation in mice. Furthermore, PYPE inactivated NF-κB and STAT3 signaling to exert anti-inflammatory and anticancer effects. Taken together, these findings indicate that PYPE may be used as a promising preventive strategy against UC and CAC.

Harringtonine: A more effective antagonist for Omicron variant.

Fusion with host cell membrane is the main mechanism of infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we propose that a new strategy to screen small-molecule antagonists blocking SARS-CoV-2 membrane fusion. Using cell membrane chromatography (CMC), we found that harringtonine (HT) simultaneously targeted SARS-CoV-2 S protein and host cell surface TMPRSS2 expressed by the host cell, and subsequently confirmed that HT can inhibit membrane fusion. HT effectively blocked SARS-CoV-2 original strain entry with the IC50 of 0.217 µM, while the IC50 in delta variant decreased to 0.101 µM, the IC50 in Omicron BA.1 variant was 0.042 µM. Due to high transmissibility and immune escape, Omicron subvariant BA.5 has become the dominant strain of the SARS-CoV-2 virus and led to escalating COVID-19 cases, however, against BA.5, HT showed a surprising effectiveness. The IC50 in Omicron BA.5 was even lower than 0.0019 µM. The above results revealed the effect of HT on Omicron is very significant. In summary, we characterize HT as a small-molecule antagonist by direct targeting on the Spike protein and TMPRSS2.

Metabolomic analysis reveals the influence of HMBOX1 on RAW264.7 cells proliferation based on UPLC-MS/MS.

Macrophages are important effector cells in tumor progression and immune regulation. Previously, we demonstrated that the transcription suppressor homeobox containing 1(HMBOX1) exhibits immunosuppressive activity in LPS-induced acute liver injury by impeding macrophage infiltration and activation. We also observed a lower proliferation in HMBOX1-overexpressed RAW264.7 cells. However, the specific mechanism was unclear. Here, a work was performed to characterize HMBOX1 function related to cell proliferation from a metabolomics standpoint by comparing the metabolic profiles of HMBOX1-overexpressed RAW264.7 cells to those of the controls. Firstly, we assessed HMBOX1 anti-proliferation activity in RAW264.7 cells with CCK8 assay and clone formation. Then, we performed metabolomic analyses by ultra-liquid chromatography coupled with mass spectrometry to explore the potential mechanisms. Our results indicated that HMBOX1 inhibited the macrophage growth curve and clone formation ability. Metabolomic analyses showed significant changes in HMBOX1-overexpressed RAW264.7 metabolites. A total of 1312 metabolites were detected, and 185 differential metabolites were identified based on the criterion of OPLS-DA VIP > 1 and p value < 0.05. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that the elevated HMBOX1 in RAW264.7 inhibited the pathways of amino acid and nucleotide metabolism. Glutamine concentrations decreased significantly in HMBOX1-overexpressed macrophages, and glutamine-related transporter SLC1A5 was also downregulated. Furthermore, SLC1A5 overexpression reversed HMBOX1 inhibition of macrophage proliferation. This study demonstrated the potential mechanism of the HMBOX1/SLC1A5 pathway in cell proliferation by regulating glutamine transportation. The results may help provide a new direction for therapeutic interventions in macrophage-related inflammatory diseases.

Evolutionary analysis of KED-rich proteins in plants.

During the course of evolution, organisms have developed genetic mechanisms in response to various environmental stresses including wounding from mechanical damage or herbivory-caused injury. A previous study of wounding response in the plant tobacco identified a unique wound-induced gene, aptly named KED due to its coding for a protein that has an unusually high content of amino acids lysine (K), glutamic acid (E) and aspartic acid (D). However, by far little is known about this intriguing gene. In this study, we investigated the evolutionary aspects of the KED-rich coding genes. We found that a consistent pattern of wound-induced KED gene expression is maintained across representative species of angiosperm and gymnosperm. KED genes can be identified in species from all groups of land plants (Embryophyta). All the KED proteins from vascular plants (Tracheophyta) including angiosperm, gymnosperm, fern and lycophyte share a conserved 19-amino acid domain near the C-terminus, whereas bryophytes (moss, liverwort and hornwort) possess KED-rich, multi-direct-repeat sequences that are distinct from the vascular plant KEDs. We detected KED-rich sequences in Charophyta species but not in Chlorophyta wherever genome sequences are available. Our studies suggest diverse and complex evolution pathways for land plant KED genes. Vascular plant KEDs exhibit high evolutionary conservation, implicating their shared function in response to wounding stress. The extraordinary enrichment of amino acids K, E and D in these groups of distinct and widely distributed proteins may reflect the structural and functional requirement for these three residues during some 600 million years of land plant evolution.

Lymphocyte subset is more suitable than systemic inflammatory response biomarker and immunoglobulin in constructing prognostic nomogram model for advanced gastric cancer.

The serum factors of inflammation are known to be useful prognostic indicators of gastric cancer (GC). However, few studies have made comparisons to screen out more suitable biomarkers for the construction of Nomogram models. In this study, 566 patients who underwent radical gastrectomy were randomly selected. We evaluated the prognostic value of markers of systemic inflammation, including WBC, NLR, PLR, circulating total T cells, CD4+T cells, CD8+T cells and CD19+B cells, serum IgA, IgM, IgE and IgG, and compared them with traditional tumor markers (CEA, CA19-9, CA72-4 and CA125). Kaplan‒Meier analysis was used to analyze the correlation between biomarkers and overall survival (OS). We used time-dependent ROC analysis to investigate the prognostic accuracy of each biomarker. The risk of death was evaluated by the Cox regression model, and the Nomogram model was constructed by R software. We found that circulating total T cells, CD8+T cells, CEA, and CA125 had statistical significance in predicting advanced GC prognosis. Circulating CD8+T cells and CA125 were continuously superior to circulating total T cells and CEA in the prediction of 5-year OS. Cox regression found that CA125, circulating CD8+T cells, sex, and lymph node metastasis rate were independent risk factors for advanced GC. Furthermore, we combined all these predictors to construct a nomogram, which can supplement the AJCC 8th system. According to the comparison with commonly used serum immune biomarkers, circulating CD8+T cells is more sensitive to advanced GC. The prediction function of the Nomogram will supplement the traditional AJCC system, which contributes to individual survival prediction.

Cross-species infection potential of avian influenza H13 viruses isolated from wild aquatic birds to poultry and mammals.

Wild aquatic birds are the primary hosts of H13 avian influenza viruses (AIVs). Herein, we performed a genetic analysis of two H13 AIVs isolated from wild birds in China and evaluated their infection potential in poultry to further explore the potential for transmission from wild aquatic birds to poultry. Our results showed that the two strains belong to different groups, one strain (A/mallard/Dalian/DZ-137/2013; abbreviated as DZ137) belongs to Group I, whereas the other strain (A/Eurasian Curlew/Liaoning/ZH-385/2014; abbreviated as ZH385) belongs to Group III. In vitro experiments showed that both DZ137 and ZH385 can replicate efficiently in chicken embryo fibroblast cells. We found that these H13 AIVs can also efficiently replicate in mammalian cell lines, including human embryonic kidney cells and Madin-Darby canine kidney cells. In vivo experiments showed that DZ137 and ZH385 can infect 1-day-old specific pathogen-free (SPF) chickens, and that ZH385 has a higher replication ability in chickens than DZ137. Notably, only ZH385 can replicate efficiently in 10-day-old SPF chickens. However, neither DZ137 nor ZH385 can replicate well in turkeys and quails. Both DZ137 and ZH385 can replicate in 3-week-old mice. Serological surveillance of poultry showed a 4.6%-10.4% (15/328-34/328) antibody-positive rate against H13 AIVs in farm chickens. Our findings indicate that H13 AIVs have the replication ability in chickens and mice and may have a risk of crossing the host barrier from wild aquatic birds to poultry or mammals in the future.

The prognostic marker elastin correlates with epithelial-mesenchymal transition and vimentin-positive fibroblasts in gastric cancer.

Elastin (ELN) fibers are essential constituents of the tumor microenvironment of gastric cancer (GC). However, few studies have investigated the clinical prognostic significance of ELN in GC. We screened for molecular markers that were highly related to distant metastasis by transcriptome sequencing. The Cancer Genome Atlas (TCGA) and Harbin Medical University (HMU) validation cohorts were used to validate ELN expression and to explore molecular mechanisms. Immunohistochemistry for ELN, vimentin (VIM), and fibroblast activation protein, and elastic fiber-specific staining were used to evaluate the relationship between ELN and prognosis. R studio was used to construct a nomogram prognostic model. In this study, we found that ELN mRNA levels were significantly higher in cancer tissues and were associated with poor prognosis in TCGA and HMU patients. Gene set enrichment analysis showed that ELN was mainly enriched in the epithelial-mesenchymal transition (EMT) pathway. The mRNA expression of ELN was positively correlated with fibroblast molecular markers, especially VIM. For validation, we collected a tissue microarray containing 180 pairs of samples. We found that ELN was positively correlated with VIM expression in cancer tissue but not in paracancerous tissues by immunohistochemistry staining. Univariate and multivariate analyses showed that the expression of ELN and lymph node metastasis rate were independent predictors for overall survival. Moreover, a nomogram model was used to evaluate the risk of death by combining the expression of ELN and lymph node metastasis rate. ELN may play an important role in the progression of GC by regulating EMT and is a useful prognostic indicator in predicting the prognosis of GC.

A bispecific nanobody dimer broadly neutralizes SARS-CoV-1 & 2 variants of concern and offers substantial protection against Omicron via low-dose intranasal administration.

Current SARS-CoV-2 Omicron subvariants impose a heavy burden on global health systems by evading immunity from most developed neutralizing antibodies and vaccines. Here, we identified a nanobody (aSA3) that strongly cross-reacts with the receptor binding domain (RBD) of both SARS-CoV-1 and wild-type (WT) SARS-CoV-2. The dimeric construct of aSA3 (aSA3-Fc) tightly binds and potently neutralizes both SARS-CoV-1 and WT SARS-CoV-2. Based on X-ray crystallography, we engineered a bispecific nanobody dimer (2-3-Fc) by fusing aSA3-Fc to aRBD-2, a previously identified broad-spectrum nanobody targeting an RBD epitope distinct from aSA3. 2-3-Fc exhibits single-digit ng/mL neutralizing potency against all major variants of concerns including BA.5. In hamsters, a single systemic dose of 2-3-Fc at 10 mg/kg conferred substantial efficacy against Omicron infection. More importantly, even at three low doses of 0.5 mg/kg, 2-3-Fc prophylactically administered through the intranasal route drastically reduced viral RNA loads and completely eliminated infectious Omicron particles in the trachea and lungs. Finally, we discovered that 2(Y29G)-3-Fc containing a Y29G substitution in aRBD-2 showed better activity than 2-3-Fc in neutralizing BA.2.75, a recent Omicron subvariant that emerged in India. This study expands the arsenal against SARS-CoV-1, provides potential therapeutic and prophylactic candidates that fully cover major SARS-CoV-2 variants, and may offer a simple preventive approach against Omicron and its subvariants.

Increased pathogenicity and aerosol transmission for one SARS-CoV-2 B.1.617.2 Delta variant over the wild-type strain in hamsters.

During the two-year pandemic of coronavirus disease 2019 (COVID-19), its causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been evolving. SARS-CoV-2 Delta, a variant of concern, has become the dominant circulating strain worldwide within just a few months. Here, we performed a comprehensive analysis of a new B.1.617.2 Delta strain (Delta630) compared with the early WIV04 strain (WIV04) in vitro and in vivo, in terms of replication, infectivity, pathogenicity, and transmission in hamsters. When inoculated intranasally, Delta630 led to more pronounced weight loss and more severe disease in hamsters. Moreover, 40% mortality occurred about one week after infection with 104 â€‹PFU of Delta630, whereas no deaths occurred even after infection with 105 â€‹PFU of WIV04 or other strains belonging to the Delta variant. Moreover, Delta630 outgrew over WIV04 in the competitive aerosol transmission experiment. Taken together, the Delta630 strain showed increased replication ability, pathogenicity, and transmissibility over WIV04 in hamsters. To our knowledge, this is the first SARS-CoV-2 strain that causes death in a hamster model, which could be an asset for the efficacy evaluation of vaccines and antivirals against infections of SARS-CoV-2 Delta strains. The underlying molecular mechanisms of increased virulence and transmission await further analysis.

Patient Toward Physician Occupational Stigma Scale: Development of the Chinese Version.

Background/Objective: Physicians' occupational stigma could eradicate physician-patient trust, threatening physicians' social status and occupational reputation. Hitherto, there has been no scale obtaining good psychometric properties to assess patients' stigma toward physicians. The present study aimed to develop the Patient toward Physician Occupational Stigma Scale (PPOSS) and examine its reliability and validity. Methods: The questionnaire comprising sociodemographic information and the PPOSS were employed to survey 645 Chinese patients in two phases. In Sample 2, the Wake Forest Physician Trust Scale (WFOTS), the Intolerance of Uncertainty Scale-12 (IUS-12), and the Brief Illness Perception Questionnaire (BIPQ) were tested. Results: The PPOSS includes 19 items subsumed into three dimensions of stereotype, discrimination, and prejudice. According to the results of confirmatory factor analysis (CFA), the three-factor model fitted well (χ2/df=2.065, RMSEA=0.057, SRMR=0.045, RFI=0.904, CFI=0.956, IFI=0.956, PNFI=0.779, PCFI=0.811). The PPOSS was significantly negatively correlated with the WFOTS, and significantly positively correlated with the IUS-12 and the BIPQ. The Cronbach's alpha coefficients for the total scale and each dimension were between 0.87 and 0.94, and the split-half reliability coefficients were between 0.84 and 0.93. Besides, the PPOSS had the measurement invariance across gender. Conclusion: With its satisfactory psychometric properties, the PPOSS can be used as an effective instrument to assess patients' stigma toward physicians.

A potent neutralizing antibody provides protection against SARS-CoV-2 Omicron and Delta variants via nasal delivery.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still rapidly spreading worldwide. Many drugs and vaccines have been approved for clinical use show efficacy in the treatment and prevention of SARS-CoV-2 infections. However, the emergence of SARS-CoV-2 variants of concern (VOCs), such as Delta (B.1.617.2) and the recently emerged Omicron (B.1.1.529), has seriously challenged the application of current therapeutics. Therefore, there is still a pressing need for identification of new broad-spectrum antivirals. Here, we further characterized a human antibody (58G6), which we previously isolated from a patient, with a broadly authentic virus-neutralizing activity that inhibits the Delta and Omicron variants with half-maximal inhibitory concentrations (IC50) of 1.69 ng/ml and 54.31 ng/ml, respectively. 58G6 shows prophylactic and therapeutic efficacy in hamsters challenged with the Delta and Omicron variants through nasal delivery. Notably, a very low dosage (2 mg/kg daily) of 58G6 efficiently prevented Omicron variant replication in the lungs. These advantages may overcome the efficacy limitation of currently approved neutralizing antibodies that can be administered only by intravenous injection. In general, 58G6 is a promising prophylactic and therapeutic candidate against current circulating VOCs and even future emerging mutants. To the best of our knowledge, 58G6 is one of the most potent neutralizing antibodies against Omicron, with a broader spectrum than those approved for clinical use. 58G6 could be developed as a nebulized therapy, which would be more cost effective and user friendly and enhance the clinical outcome compared to that obtained with direct nasal delivery.