Preclinical evaluation of the SARS-CoV-2 Mpro inhibitor RAY1216 shows improved pharmacokinetics compared with nirmatrelvir.

Although vaccines are available for SARS-CoV-2, antiviral drugs such as nirmatrelvir are still needed, particularly for individuals in whom vaccines are less effective, such as the immunocompromised, to prevent severe COVID-19. Here we report an α-ketoamide-based peptidomimetic inhibitor of the SARS-CoV-2 main protease (Mpro), designated RAY1216. Enzyme inhibition kinetic analysis shows that RAY1216 has an inhibition constant of 8.4 nM and suggests that it dissociates about 12 times slower from Mpro compared with nirmatrelvir. The crystal structure of the SARS-CoV-2 Mpro:RAY1216 complex shows that RAY1216 covalently binds to the catalytic Cys145 through the α-ketoamide group. In vitro and using human ACE2 transgenic mouse models, RAY1216 shows antiviral activities against SARS-CoV-2 variants comparable to those of nirmatrelvir. It also shows improved pharmacokinetics in mice and rats, suggesting that RAY1216 could be used without ritonavir, which is co-administered with nirmatrelvir. RAY1216 has been approved as a single-component drug named 'leritrelvir' for COVID-19 treatment in China.

Development and validation of a nomogram for predicting overall survival in patients with sinonasal mucosal melanoma.

BACKGROUND: Sinonasal mucosal melanoma (SNMM) is a relatively rare malignant tumour with a poor prognosis. This study was designed to identify prognostic factors and establish a nomogram model to predict the overall survival (OS) of patients with SNMM. METHODS: A total of 459 patients with SNMM were selected from the Surveillance, Epidemiology, and End Results (SEER) database as the training cohort. Univariate and multivariate Cox regression analyses were used to screen for independent factors associated with patient prognosis and develop the nomogram model. In addition, external validation was performed to evaluate the effectiveness of the nomogram with a cohort of 34 patients with SNMM from Peking Union Medical College Hospital. RESULTS: The median OS in the cohort from the SEER database was 28 months. The 1-year, 3-year and 5-year OS rates were 69.8%, 40.4%, and 30.0%, respectively. Multivariate Cox regression analysis indicated that age, T stage, N stage, surgery and radiotherapy were independent variables associated with OS. The areas under the receiver operating characteristic curves (AUCs) of the nomograms for predicting 1-, 3- and 5-year OS were 0.78, 0.71 and 0.71, respectively, in the training cohort. In the validation cohort, the area under the curve (AUC) of the nomogram for predicting 1-, 3- and 5-year OS were 0.90, 0.75 and 0.78, respectively. Patients were classified into low- and high-risk groups based on the total score of the nomogram. Patients in the low-risk group had a significantly better survival prognosis than patients in the high-risk group in both the training cohort (P < 0.0001) and the validation cohort (P = 0.0016). CONCLUSION: We established and validated a novel nomogram model to predict the OS of SNMM patients stratified by age, T stage, N stage, surgery and radiotherapy. This predictive tool is of potential importance in the realms of patient counselling and clinical decision-making.

Discovery of a Macrocyclic Influenza Cap-Dependent Endonuclease Inhibitor.

Influenza viruses (IFVs) have caused several pandemics and have claimed numerous lives since their first record in the early 20th century. While the outbreak of COVID-19 seemed to expel influenza from the sight of people for a short period of time, it is not surprising that it will recirculate around the globe after the coronavirus has mutated into a less fatal variant. Baloxavir marboxil (1), the prodrug of baloxavir (2) and a cap-dependent endonuclease (CEN) inhibitor, were approved by the FDA for the first treatment in almost 20 years. Despite their high antiviral potency, drug-resistant variants have been observed in clinical trials. Herein, we report a novel CEN inhibitor 8 with a delicately designed macrocyclic scaffold that exhibits a significantly smaller shift of inhibitory activity toward baloxavir-resistant variants.

Infratemporal Fossa Metastasis of Non-Small-Cell Lung Adenocarcinoma: A Case Report and Literature Review.

Neoplasms in the infratemporal fossa (ITF) are rare and insidious lesions that cause various symptoms due to involvement of the temporomandibular joint (TMJ), paranasal sinuses, and orbit. Here, we report a case of metastatic non-small cell lung adenocarcinoma in the ITF. The patient presented with facial pain and limited mouth opening, which did not respond to treatment for TMJ disorder, and a neoplasm was discovered in the ITF through medical imaging. With an open biopsy, the diagnosis was finalized. This report suggested that the physician should consider lesions in the ITF when facial pain and limited mouth opening failed local treatment, and distant metastasis of malignant tumor should be alerted. We also reviewed the literature regarding metastatic cancer to the ITF.

Ambient Phosphor with High Efficiency and Long Lifetime in Poly(Methyl Methacrylate) Through Charge-Transfer-Mediated Triplet Exciton Formation for Photolithography Applications.

Currently, purely organic compounds showing ambient phosphorescence with high efficiency (ΦP ) and ultra-long lifetime (τP ) are quite rare and often need to be achieved in hydrophilic poly(vinyl alcohol)-based hosts. This severely limits their applications. Here, we provide a solution to this issue by constructing an ortho-linked donor-acceptor (D-A) dyad whose D moiety has not only a long-lived T1 state to achieve a long τP , but also a Tn state that is close to the S1 state of the dyad to trigger effective spin-orbit charge transfer intersystem crossing (SOCT-ISC). The rationality of this strategy was validated by a new phosphor OF-BCz that is able to show a τP of 1.92 s and a ΦP of 30 % even in a less rigid matrix of poly(methyl methacrylate) (PMMA). Excitingly, OF-BCz exhibited its potential as both a photocuring initiator and an in situ quality indicator, allowing for the visual detection of defects in photolithographic patterning.

Multiplex immunohistochemistry defines two cholesterol metabolism patterns predicting immunotherapeutic outcomes in gastric cancer.

BACKGROUND: The role of cholesterol metabolism in gastric cancer (GC) and its implications for tumor characteristics and immunotherapy response remain poorly understood. In this study, our aim was to investigate this role, identify associated metabolic subtypes, and assess their clinical implications in GC. METHODS: We conducted a comprehensive analysis of cholesterol metabolism genes (CMGs) using transcriptomic data from TCGA and GEO. Based on 23 representative CMGs, we classified GC into metabolic subtypes. We evaluated clinical features and immune cell infiltration between these subtypes. Additionally, we identified a CMG signature and assessed its clinical relevance in GC. We retrospectively enrolled thirty-five GC patients receiving chemotherapy plus a PD-1 inhibitor to assess the CMG signature using multiplex immunohistochemistry. RESULTS: Our analysis revealed two cholesterol metabolism subtypes in GC: Cholesterol Metabolism Type 1 (CMT1) and Cholesterol Metabolism Type 2 (CMT2). These subtypes exhibited distinct patterns: CMT1 indicated heightened cholesterol biosynthesis, while CMT2 showed abnormal cholesterol transport. CMT2 was associated with unfavorable clinical features, enriched malignant pathways, and a pro-tumor immune microenvironment. Furthermore, we developed a five-CMG prognostic signature (ABCA1, NR1H3, TSPO, NCEH1, and HMGCR) that effectively predicted the prognosis of patients with GC and their response to chemotherapy plus a PD-1 inhibitor. This signature was validated in a clinical cohort using multiplex immunohistochemistry. CONCLUSION: Our results highlight the effectiveness of cholesterol metabolism patterns as biomarkers for predicting the prognosis and immunotherapy response in GC. The expression of cholesterol metabolism genes and the assessment of cholesterol metabolism patterns have the potential to predict the outcome of immunotherapy and guide treatment strategies.

Waste biomass-derived N, P co-doping carbon aerogel-coated CoxFe1-xP with modulated electron density for efficient electrooxidation of contaminants.

Developing low-cost, green, high-performing electrode materials to address environmental pollutants and the energy crisis is significant but challenging. Herein, the bimetallic iron cobalt phosphide coated in waste biomass-derived N, P co-doping carbon (CoxFe1-xP@NPC) is constructed. Furthermore, the active site density and the water decomposition energy barrier of surface-coated NPC are modulated by optimizing the electronic structure of CoxFe1-xP via doping engineering. The Fe-modulated CoxFe1-xP@NPC exhibits a hierarchical porous self-supporting structure and excellent physical & chemical properties with excellent electrooxidation performance, achieving over 95% removal of TCH within 60 min. The density functional theory (DFT) calculations further confirms that N carries more positive charge and P carries more negative charge in the NPC of CoxFe1-xP@NPC with Fe modulation, which can promote the adsorption and dissociation of water molecules. Of note, Co0.75Fe025P@NPC displays a low water dissociation energy barrier to produce ·OH and a high energy barrier to produce O2 than its counterparts. This study offers new insight into controllable modulation of biomass carbon-based composite electrode catalytic activity for high-efficiency degradation of contaminants.

Discovery of novel bicyclic[3.3.0]proline peptidyl α-ketoamides as potent 3CL-protease inhibitors for SARS-CoV-2.

The outbreak of SARS-CoV-2 has caused global crisis on health and economics. The multiple drug-drug interaction risk associated with ritonavir warrants specialized assessment before using Paxlovid. Here we report a multiple-round SAR study to provide a novel bicyclic[3.3.0]proline peptidyl α-ketoamide compound 4a, which is endowed with excellent antiviral activities and pharmacokinetic properties. Also, in vivo HCoV-OC43 neonatal mice model demonstrated compound 4a has good in vivo efficacy. Based on these properties, compound 4a worth further SAR optimization with the goal to develop compounds with better pharmacokinetic properties and finally to realize single agent efficacy in human.

Role of CD19+ CD5+ CD1d+ Bregs in maintaining the Th17/Treg balance in mice with systemic lupus erythematosus complicated with atherosclerosis.

OBJECTIVE: In this study, we aimed to investigate Bregs, their regulatory effects on Th17/Treg cell balance, and the release of downstream inflammatory factors in a mouse model of low-density lipoprotein receptor (LDLr)-/- + Pristane. METHODS: After the establishment of the mouse model of systemic lupus erythematosus (SLE) complicated with atherosclerosis (AS), 8-week-old LDLr-/- + Pristane mice (n = 10) were included in the SLE + AS group. Furthermore, 8-week-old MRL/lpr and C57 mice were used as the SLE and normal control groups, respectively (n = 10 per group). After feeding the mice a high-fat diet for 14 weeks, peripheral blood and spleen of mice were collected, and Bregs, Th17, and Treg cells and related inflammatory factors were detected by flow cytometry, enzyme-linked immunosorbent assay, and reverse-transcription polymerase chain reaction. RESULTS: The number of Bregs and Tregs in spleen lymphocytes of SLE + AS mice significantly decreased compared with the C57 group (p < .05), whereas the number of Th17 cells significantly increased (p = .000). Furthermore, the proportion of Bregs showed a negative correlation with the Th17/Treg ratio (p = .03). Mice in the SLE + AS group showed higher serum interleukin (IL)-10, IL-17, and tumor necrosis factor-α levels than those in the SLE and C57 groups (p < .05). Furthermore, IL-35 and transforming growth factor (TGF)-ß expression was reduced in the SLE + AS group compared with the C57 group (p < .05). CONCLUSIONS: The proportion of Breg decreases was negatively associated with increased Th17/Treg which was increased in SLE + AS mice, indicating that Bregs may regulate Th17/Treg cell homeostasis and cytokine release via IL-35 and TGF-ß production.

Adverse Events for Monoclonal Antibodies in Patients with Allergic Rhinitis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

(1) Background: Allergic rhinitis (AR) is a common disease in otolaryngology and novel biological therapies are required for clinical needs. To assess the tolerability of monoclonal antibodies, justifying their clinical applications, we presented a comprehensive safety profile of biologics in AR; (2) Methods: A systematic literature search was conducted following PRISMA guidelines for randomized clinical trials comparing monoclonal antibodies and placebo in AR. PubMed, Web of Science, Medline, and Cochrane were searched up until 9 January 2023. Among 3590 records in total, 12 studies with more than 2600 patients were included. Quality was assessed for all studies using Cochrane risk-of-bias tool for randomized trials, and subgrouped meta-analysis was performed; (3) Results: We accomplished an up-to-date literature overview and analysis on adverse events of monoclonal antibodies in AR. Total, common, severe, discontinuation-causing, and serious adverse events failed to reach statistical significance. Country was an essential factor for heterogeneity, and urticaria was the adverse event at highest risk (RR 2.81, 95% CI 0.79-9.95); (4) Conclusions: Monoclonal antibodies are considered well tolerated and relatively safe in patients with AR. The regions of patients and hypersensitive adverse reactions such as urticaria require a special caution in biological treatments in AR.

Sinonasal NUT carcinoma: A retrospective case series from a single institution.

Purpose: Nuclear protein in testis (NUT) carcinoma is a rare, aggressive tumor defined by the presence of NUT gene rearrangement. The aim of this study was to describe the clinical, radiologic, and biological features of sinonasal NUT carcinoma. Methods: We retrospectively investigated NUT expression with clinicopathologic features in 145 cases with sinonasal malignancies diagnosed from January 2017 to December 2021 and reviewed the reported cases. Results: Three (3/145, 2.07%) cases showed strong nuclear expression for NUT immunohistochemical, including one male and two females with ages from 37 to 57 years (mean, 45.33 years). All three cases involved the nasal cavity and sinuses; one of them involved the orbit and intracranial area. Histologically, all subjects showed poorly differentiated, small round cell morphology with distinct nuclei. All patients received surgery and chemoradiotherapy. One patient died of the disease 13 months after diagnosis, and two survived 12 and 15 months, respectively, without evidence of tumor recurrence. 51 cases of sinonasal NUT carcinoma (mean age 40.96 years) have been described to date. Among them, 28 are male, and 23 are female. Most cases expressed p63, AE1/AE3, as well as p40. Conclusion: NUT carcinoma is a rare and aggressive disease with a poor prognosis. It is crucial to perform NUT rearrangement-related tests for differential diagnosis of poorly differentiated/undifferentiated tumors in the nasal cavity and sinuses.

2-Aminopyrimidine derivatives as selective dual inhibitors of JAK2 and FLT3 for the treatment of acute myeloid leukemia.

Dual inhibitors of JAK2 and FLT3 can synergistically control the development of acute myeloid leukemia (AML), and overcome secondary drug resistance of AML that is associated with FLT3 inhibition. We therefore designed and synthesized a series of 4-piperazinyl-2-aminopyrimidines as dual inhibitors of JAK2 and FLT3, and improved their selectivity for JAK2. Screening cascades revealed that compound 11r exhibited inhibitory activity with IC50 values of 2.01, 0.51, and 104.40 nM against JAK2, FLT3, and JAK3, respectively. Compound 11r achieved a high selectivity for JAK2 at a ratio of 51.94, and also showed potent antiproliferative activity in HEL (IC50 = 1.10 µM) and MV4-11 (IC50 = 9.43 nM) cell lines. In an in vitro metabolism assay, 11r exhibited moderate stability in human liver microsomes (HLMs), with a half-life time of 44.4 min, and in rat liver microsomes (RLMs), with a half-life of 143 min. In pharmacokinetic studies, compound 11r showed moderate absorption (Tmax = 5.33 h), with a peak concentration of 38.7 ng/mL and an AUC of 522 ng h/mL in rats, and an oral bioavailability of 25.2%. In addition, 11r induced MV4-11 cell apoptosis in a dose-dependent manner. These results indicate that 11r is a promising selective JAK2/FLT3 dual inhibitor.

Favorable pregnancy outcomes in two patients with systemic lupus erythematosus treated with belimumab.

BACKGROUND: Systemic lupus erythematosus (SLE) is associated with poor pregnancy outcomes and complications. Belimumab can significantly improve disease activity in patients with SLE. However, there is insufficient evidence to prove the absolute safety of belimumab treatment during pregnancy. CASE SUMMARY: A 37-year-old woman was diagnosed with SLE after a renal puncture biopsy in 2012. The other patient was a 25-year-old woman. She was diagnosed with SLE at 19 years of age. They were treated by standard therapy in the early stage of treatment. The first patient has multiple histories of miscarriages or abortions at different gestational ages caused by SLE activity. The other patient also has persistent thrombocytopenia due to SLE flare. In our patients, SLE was poorly controlled by standard therapy. We initiated belimumab treatment during pregnancy because the benefits of treating SLE outweighed the risks to the fetus. The first patient was admitted to the first belimumab infusion at approximately 14 weeks of gestation. The other patient was admitted to the first belimumab infusion at approximately 12 weeks of gestation. Although our patients did not show complete disease remission during belimumab treatment, neither had serious adverse reactions or adverse pregnancy events, and their babies were in good conditions at birth. CONCLUSION: We present 2 cases of pregnant women with SLE who were treated with belimumab. Both were able to deliver their babies successfully without any complications.

The mediating effect of psychological resilience on empathy and professional identity of Chinese nursing students: A structural equation model analysis.

BACKGROUND: Previous studies have shown that empathy has a positive impact on the professional identity of nursing students. And developing psychological resilience can improve the professional identity of nursing students. However, studies investigating the mechanism of the relationship between empathy and psychological resilience on professional identity remain few. PURPOSE: Among Chinese nursing students, we sought to determine whether psychological resilience mediates the association between empathy and professional identity. METHODS: A total of 495 undergraduate and postgraduate nursing students in a medical university nursing college in Hefei were investigated by demographic data questionnaire, nursing students' empathy scale, nursing students' professional identity questionnaire, and psychological resilience questionnaire. Structural equation modeling was used to analyze the mediating effect of psychological resilience between empathy and the professional identity of nursing students. RESULTS: The total score of professional identity of nursing students was 57.07 ± 10.38. Psychological resilience (r = 0.316, P < 0.01) and professional identity (r = 0.313, P < 0.01) both had positive correlations with empathy, respectively. Additionally, there was a strong correlation between psychological resilience and professional identity (r = 0.488, P < 0.01). Empathy had an indirect effect on professional identity through psychological resilience, with a direct effect of 0.256 and an indirect effect of 0.145, and the indirect effect accounted for 36.16 % of the total effect. CONCLUSION: Nursing educators should pay attention to the cultivation of empathy ability and psychological resilience to enhance nursing students' professional identity.

Single-cell profiling identifies mechanisms of inflammatory heterogeneity in chronic rhinosinusitis.

The heterogeneous cellular microenvironment of human airway chronic inflammatory diseases, including chronic rhinosinusitis (CRS) and asthma, is still poorly understood. Here, we performed single-cell RNA sequencing (scRNA-seq) on the nasal mucosa of healthy individuals and patients with three subtypes of CRS and identified disease-specific cell subsets and molecules that specifically contribute to the pathogenesis of CRS subtypes. As such, ALOX15+ macrophages contributed to the type 2 immunity-driven pathogenesis of one subtype of CRS, eosinophilic CRS with nasal polyps (eCRSwNP), by secreting chemokines that recruited eosinophils, monocytes and T helper 2 (TH2) cells. An inhibitor of ALOX15 reduced the release of proinflammatory chemokines in human macrophages and inhibited the overactivation of type 2 immunity in a mouse model of eosinophilic rhinosinusitis. Our findings advance the understanding of the heterogeneous immune microenvironment and the pathogenesis of CRS subtypes and identify potential therapeutic approaches for the treatment of CRS and potentially other type 2 immunity-mediated diseases.

Multiple perspectives reveal the gut toxicity of polystyrene microplastics on Eisenia fetida: Insights into community signatures of gut bacteria and their translocation.

The gut is the primary pathway by which soil animals are exposed to microplastics (MPs). However, the gut toxicity of MPs has not been elucidated in earthworms. Herein, we aimed to study the gut toxicity (e.g., gut barrier dysfunction, gut bacterial translocation, and pathogen invasion) of polystyrene microplastics (PS-MPs) on Eisenia fetida and its relationship with gut bacteria. We found that PS-MPs exposure caused gut barrier damage to Eisenia fetida. This damage included apparent injury of gut epithelial cells and significantly lower transcription levels of genes coding for gut tight junction (TJ)-related proteins. We then observed significantly increased levels of bacterial lipopolysaccharide (LPS) and gut bacterial load, indicating the occurrence of gut bacterial translocation and related barrier damage. Subsequently, antibacterial immune responses were activated and accompanied by a failure of the antioxidant defense system, indicating that pathogen invasion might occur. Gut barrier damage could weaken host selective pressures (deterministic process) on gut bacteria, such as particular pathogens. Indeed, members of Proteobacteria, e.g., Aeromonas and Escherichia/Shigella, regarded as potential opportunistic pathogens, were remarkable signatures of groups exposed to PS-MPs. These potential opportunistic gut bacteria were pivotal contributors to gut TJ damage and gut bacterial translocation resulting from PS-MPs exposure. In addition, the gut bacterial networks of PS-MPs exposure groups were more uncomplicated than those of the control group, but more negative interactions were easy to observe. In conclusion, our work sheds light on the molecular mechanism of earthworm gut toxicity caused by PS-MPs exposure and provides a prospective risk assessment of MPs in soil ecosystems.

Increased Gray Matter Volume Induced by Chinese Language Acquisition in Adult Alphabetic Language Speakers.

It is interesting to explore the effects of second language (L2) acquisition on anatomical change in brain at different stages for the neural structural adaptations are dynamic. Short-term Chinese training effects on brain anatomical structures in alphabetic language speakers have been already studied. However, little is known about the adaptations of the gray matter induced by acquiring Chinese language for a relatively long learning period in adult alphabetic language speakers. To explore this issue, we recruited 38 Indian overseas students in China as our subjects. The learned group included 17 participants who had learned Mandarin Chinese for an average of 3.24 years and achieved intermediate Chinese language proficiency. The control group included 21 subjects who had no knowledge about Chinese. None of the participants had any experience in learning logographic and tonal language before Chinese learning. We found that (1) the learned group had significantly greater gray matter volume (GMV) in the left lingual gyrus (LG) compared with the control group; (2) the Chinese characters' reading accuracy was significantly and positively correlated to the GMV in the left LG and fusiform gyrus (FG) across the two groups; and (3) in the learned group, the duration of Chinese learning was significantly and positively correlated with the GMV in the left inferior frontal gyrus (IFG) after correction for multiple comparisons with small volume corrections. Our structural imaging findings are in line with the functional imaging studies reporting increased brain activation induced by Chinese acquisition in alphabetic language speakers. The regional gray matter changes reflected the additional requirements imposed by the more difficult processing of Chinese characters and tones. The present study also show that the biological bases of the adaptations induced by a relatively long period of Chinese learning were limited in the common areas for first and foreign language processing.

The MdBBX22-miR858-MdMYB9/11/12 module regulates proanthocyanidin biosynthesis in apple peel.

Proanthocyanidins (PAs) have antioxidant properties and are beneficial to human health. The fruit of apple (Malus × domestica Borkh.), especially the peel, is rich in various flavonoids, such as PAs, and thus is an important source of dietary antioxidants. Previous research on the regulation of PAs in apple has mainly focussed on the transcription level, whereas studies conducted at the post-transcriptional level are relatively rare. In this study, we investigated the function of mdm-miR858, a miRNA with multiple functions in plant development, in the peel of apple fruit. We showed that mdm-miR858 negatively regulated PA accumulation by targeting MdMYB9/11/12 in the peel. During fruit development, mdm-miR858 expression was negatively correlated with MdMYB9/11/12 expression and PA accumulation. A 5'-RACE experiment, GUS staining assays and transient luminescent assays indicated that mdm-miR858 cleaved and inhibited the expression of MdMYB9/11/12. Overexpression of mdm-miR858 in apple calli, tobacco and Arabidopsis reduced the accumulation of PAs induced by overexpression of MdMYB9/11/12. Furthermore, we found that MdBBX22 bound to the mdm-miR858 promoter and induced its expression. Overexpression of MdBBX22 induced the expression of mdm-miR858 to inhibit the accumulation of PAs in apple calli overexpressing MdMYB9/11/12. Under light stress, MdBBX22 induced mdm-miR858 expression to inhibit PA accumulation and thereby indirectly enhanced anthocyanin synthesis in the peel. The present results revealed that the MdBBX22-miR858-MdMYB9/11/12 module regulates PA accumulation in apple. The findings provide a reference for further studies of the regulatory mechanism of PA accumulation and the relationship between PAs and anthocyanins.