Causal relationship between the immune cells and ankylosing spondylitis: univariable, bidirectional, and multivariable Mendelian randomization.

Background: Ankylosing spondylitis (AS) is an autoimmune disease that affects millions of individuals. Immune cells have been recognized as having a crucial role in the pathogenesis of AS. However, their relationship has not been fully explored. Methods: We chose to employ Mendelian randomization (MR) to investigate the potential correlation between immune cells and AS. We sourced the data on immune cells from the latest genome-wide association studies (GWASs). We obtained data on AS from the FinnGen consortium. Our comprehensive univariable MR analysis covered 731 immune cells to explore its potential causal relationship with AS. The primary analysis method was inverse-variance weighted (IVW). Additionally, we used Cochran's Q test and the MR-Egger intercept test to assess the presence of pleiotropy and heterogeneity. We examined whether our results could be influenced by individual single-nucleotide polymorphisms (SNPs) using the leave-one-out test. We conducted a bidirectional MR to investigate the reverse relationship. We also applied multivariable MR to decrease the potential influence between the immune cells. Results: Overall, our univariable MR analysis revealed eight immune cells associated with AS. Among these, four immune cells contributed to an increased risk of AS, while four immune cells were identified as protective factors for AS. However, the Bonferroni test confirmed only one risk factor and one protective factor with a significance level of p < 6.84E-05. CD8 on effector memory CD8+ T cell could increase the risk of AS (p: 1.2302E-05, OR: 2.9871, 95%CI: 1.8289-4.8786). HLA DR on CD33dim HLA DR+ CD11b+ could decrease the risk of AS (p: 1.2301E-06, OR: 0.5446, 95%CI: 0.4260-0.6962). We also identified a bidirectional relationship between CD4 on CD39+ activated CD4 regulatory T cells and AS utilizing the bidirectional MR. To address potential confounding among immune cells, we employed multivariable MR analysis, which revealed that only one immune cell had an independent effect on AS. HLA DR on CD33dim HLA DR+ CD11b+ could decrease the risk of AS (p: 2.113E-06, OR: 0.0.5423, 95%CI: 0.4210-0.6983). Our findings were consistently stable and reliable. Conclusions: Our findings indicated a potential link between immune cells and AS, which could provide a new idea for future research. Nevertheless, the specific underlying mechanisms require further exploration.

Development and validation of a nomogram to predict the risk of constipation after lumbar interbody fusion surgery.

INTRODUCTION: To understand the incidence of postoperative constipation and the risk factors of constipation in patients with lumbar interbody fusion, we constructed and verified the constipation risk prediction model, so as to provide reference for the prevention and treatment of postoperative constipation. METHODS: The data of patients undergoing lumbar interbody fusion in our hospital were retrospectively analyzed from December 2021 to December 2022. According to postoperative constipation, the patients were divided into constipation group and non-constipation group. Univariate logistic regression analysis and multivariate logistic regression analysis were used to determine independent risk factors for postoperative constipation. Based on independent risk factors, a nomogram was developed to predict the risk of constipation after lumbar interbody fusion. The prediction performance was assessed using receiver operating characteristic curve (ROC), calibration curve and decision curve analysis (DCA). Finally, bootstrapping method for internal validation was further evaluated the nomogram. RESULTS: A total of 282 patients participated in the study. 176 patients (62.41%) after lumbar interbody occurred constipation, and 106 patients were asymptomatic. Multivariate regression analysis showed independent risk factors, including the use of calcium channel blockers, polypharmacy, postoperative bed time, and constipation history. Multivariate regression analysis was used to establish the model. The C-index of the nomogram was 0.827 (95% CI 0.779-0.875), and the C-index of interval bootstrapping validation was 0.813 (95% CI 0.765-0.861), and the area under the AUC was 0.800. The nomogram showed good discrimination ability. CONCLUSIONS: The use of calcium channel blockers, polypharmacy, postoperative bed time, and history of constipation are independent risk factors for postoperative constipation in patients undergoing lumbar interbody fusion. The constructed risk prediction model has good discriminative ability.

Posterior Lateral Endoscopic Cervical Discectomy Through a Lateral Mass Approach in the Treatment of Cervical Spondylotic Radiculopathy.

OBJECTIVE: The present study outlines the feasibility, safety, and short-term clinical outcomes of posterior lateral endoscopic cervical discectomy (PLECD) through a lateral mass approach for treating cervical spondylotic radiculopathy (CSR). METHODS: This single-center retrospective observational study involved 30 patients with single-level CSR who had failed conservative treatment and presented with clinical symptoms consistent with imaging findings undergoing PLECD via a lateral mass approach. Primary outcomes included the visual analog scale (VAS) for neck and arm pain, the Japanese Orthopedic Association (JOA) score, and the modified MacNab criteria. Radiographic follow-up consisted of static and dynamic cervical radiographs and computed tomographic scans. RESULTS: Thirty patients (13 men and 17 women; mean age 48.8 ± 11.9 years) underwent this procedure, and the mean operative time was 74.90 ± 13.52 minutes. Mean follow-up was 7.37 ± 2.17 months. The VAS scores for the neck and arm decreased significantly at the last follow-up (neck, 26.80 ± 4.75 to 9.87 ± 1.78; arm, 71.30 ± 8.48 to 14.73 ± 4.00) (P < 0.05). The JOA score also decreased from 13.47 ± 1.36 to 15.90 ± 0.92 at the last follow-up (P < 0.05). Twenty-nine patients demonstrated satisfactory outcomes based on the modified MacNab criteria at the last follow-up. All patients exhibited a positive clinical response, experiencing relief from symptoms. Postoperative computed tomography (CT) scans confirmed the complete removal of lesions. CONCLUSIONS: PLECD through a lateral mass approach, as an alternative to conventional "keyhole" approaches, proves to be a novel and viable therapeutic option for CSR, demonstrating both high efficacy and safety.

Lanthanide/B(C6F5)3-Promoted Hydroboration Reduction of Indoles and Quinolines with Pinacolborane.

We have developed a lanthanide/B(C6F5)3-promoted hydroboration reduction of indoles and quinolines with pinacolborane (HBpin). This reaction provides streamlined access to a range of nitrogen-containing compounds in moderate to excellent yields. Large-scale synthesis and further transformations to bioactive compounds indicate that the method has potential practical applications. Preliminary mechanistic studies suggest that amine additives promote the formation of indole-borane intermediates, and the lanthanide/B(C6F5)3-promoted hydroboration reduction proceeds via hydroboration of indole-borane intermediates with HBpin and in situ-formed BH3 species, followed by the protodeborylation process.

Molecular mechanism of interleukin-17A regulating airway epithelial cell ferroptosis based on allergic asthma airway inflammation.

Interleukin-17A (IL-17A) levels are elevated in patients with asthma. Ferroptosis has been identified as the non-apoptotic cell death type associated with asthma. Data regarding the relation of ferroptosis with asthma and the effect of IL-17A on modulating ferroptosis in asthma remain largely unclear. The present work focused on investigating the role of IL-17A in allergic asthma-related ferroptosis and its associated molecular mechanisms using public datasets, clinical samples, human bronchial epithelial cells, and an allergic asthma mouse model. We found that IL-17A was significantly upregulated within serum in asthma cases. Adding IL-17A significantly increased ferroptosis within human bronchial epithelial cells (BEAS-2B). In ovalbumin (OVA)-induced allergic asthmatic mice, IL-17A regulated and activated lipid peroxidation induced ferroptosis, whereas IL-17A knockdown effectively inhibited ferroptosis in vivo by protection of airway epithelial cells via the xCT-GSH-GPX4 antioxidant system and reduced airway inflammation. Mouse mRNA sequencing results indicated that the tumor necrosis factor (TNF) pathway was the differential KEGG pathway in the OVA group compared to healthy controls and the OVA group compared to the IL-17A knockout OVA group. We further used N-acetylcysteine (TNF inhibitor) to inhibit the TNF signaling pathway, which was found to protect BEAS-2B cells from IL-17A induced lipid peroxidation and ferroptosis damage. Our findings reveal a novel mechanism for the suppression of ferroptosis in airway epithelial cells, which may represent a new strategy for the use of IL-17A inhibitors against allergic asthma.

Discovery of a potent inhibitor targeting the cap-binding domain of the PB2 subunit of influenza RNA-dependent RNA polymerase.

Influenza pandemics have emerged as a significant global public health and security concern. PB2, a crucial subunit of the influenza RNA-dependent RNA polymerase (RdRP), has been identified as a promising target for influenza treatment. We herein report the discovery of a potent novel PB2 inhibitor, 7-51A, with a KD value of 1.64 nM as determined by ITC. The high activity of 7-51A was elucidated by the co-crystal structure of the PB2-7-51A complex, and comparative analysis revealed unique interactions that had never been observed before. The preliminary pharmacological evaluation indicated that 7-51A exhibited commendable cellular safety, hepatic microsomal metabolic safety and stability. Collectively, 7-51A was found to be an effective PB2 inhibitor and could be used as a lead compound for further studies.

Impact of carbon lock-in on green economic efficiency: Evidence from Chinese provincial data.

Carbon lock-in is a major obstacle to transforming carbon-based energy systems toward carbon peaking and neutralization, affecting the green economy. However, its impacts and paths on green development are unclear, and it is difficult to represent carbon lock-in using a single indicator. This study measures five types of carbon lock-ins and their comprehensive effect using the entropy index of 22 indirect indicators in 31 Chinese provinces during 1995-2021. Moreover, green economic efficiencies are measured using a fuzzy slacks-based model considering undesirable outputs. The panel Tobit models are used to test the impacts of carbon lock-ins on green economic efficiencies and their decompositions. Our results show that provincial carbon lock-ins in China range from 0.20 to 0.80, with notable type and regional differences. Overall carbon lock-in levels are similar, but the severity of different carbon lock-in types varies, with social behavior being the most serious. However, the overall trend of carbon lock-ins is declining. Low pure green economic efficiencies, rather than scale efficiencies, contribute to China's worrisome green economic efficiencies, but they are decreasing and accompanied by regional gaps. Carbon lock-in hinders green development, but a specific analysis is needed for different carbon lock-in types and development phases. It is biased to assume that all carbon lock-ins hinder sustainable development, as some are even necessary. The impacts of carbon lock-in on green economic efficiency depend more on its effect on technology than on scale change. Implementing various measures to unlock carbon and maintaining reasonable levels of carbon lock-in can promote high-quality development. This paper may promote the development of new unlocking CLI measures and sustainable development policies.

Mechanism of action and side effects of colchicine based on biomechanical properties of cells.

Many diseases are related to changes in the biomechanical properties of cells; their study can provide a theoretical basis for drug screening and can explain the internal working of living cells. In this study, the biomechanical properties of nephrocytes (VERO cells), hepatocytes (HL-7702 cells), and hepatoma cells (SMCC-7721 cells) in culture were detected by atomic force microscopy (AFM) to analyse the side effects of colchicine at different concentrations (0.1 µg/mL (A) and 0.2 µg/mL (B)) at the nanoscale for 2, 4 and 6 h. Compared with the corresponding control cells, the damage to the treated cells increased in a dose-dependent manner. Among normal cells, the injury of nephrocytes (VERO cells) was markedly worse than that of hepatocytes (HL-7702 cells) in both colchicine solutions A and B. Based on the analyses of biomechanical properties, the colchicine solution reduced the rate of division and inhibited metastasis of SMCC-7721 cells. By comparing these two concentrations, we found that the anticancer effect of colchicine solution A was greater than that of solution B. Studying the mechanical properties of biological cells can help understand the mechanism of drug action at the molecular level and provide a theoretical basis for preventing the emergence and diagnosis of diseases at the nanoscale.

Salusins: advance in cardiovascular disease research.

Salusins are discovered in 2003 and divided into salusin-α and salusin-ß, which are bioactive peptides with hemodynamic and mitotic activity and mainly distributed in plasma, urine, endocrine glands and kidneys. A large number of studies have shown that salusins can regulate lipid metabolism, inflammatory response and vascular proliferation. Despite the profound and diverse physiological properties of salusins, the exact mechanism of their cardiovascular effects remains to be determined. The potential mechanisms of action of salusins in cardiovascular-related diseases such as atherosclerosis, hypertension, heart failure, myocardial infarction and myocarditis, and their use as biomarkers of cardiovascular disease are discussed. This review aims to provide a new strategy for the diagnosis and prevention of clinical cardiovascular diseases.

Preliminary MRI Study of Extracellular Volume Fraction for Identification of Lymphovascular Space Invasion of Cervical Cancer.

BACKGROUND: Lymphovascular space invasion (LVSI) is a risk factor for poor prognosis of cervical cancer. Preoperative identification of LVSI is very difficult. PURPOSE: To evaluate the potential of extracellular volume (ECV) fraction based on T1 mapping in preoperative identification of LVSI in cervical cancer compared with dynamic contrast-enhanced MRI (DCE-MRI). STUDY TYPE: Retrospective. SUBJECTS: A total of 79 patients (median age 54 years) with cervical cancer were classified into LVSI group (n = 29) and without LVSI group (n = 50) according to postoperative pathology. FIELD STRENGTH/SEQUENCE: A 3-T, noncontrast and contrast-enhanced T1 mapping performed with volume interpolated breath hold examination (VIBE) sequence, DCE-MRI applied with 3D T1-weighted VIBE sequence. ASSESSMENT: Regions of interest along the medial edge of the lesion were drawn on slices depicting the maximum cross-section of the tumor. The noncontrast and contrast-enhanced T1 value of the tumor and arteries in the same slice were measured, and ECV was calculated from T1 values. The parametric maps (Ktrans , kep , and ve ) derived from DCE-MRI standard Toft's model were evaluated. STATISTICAL TESTS: ECV, Ktrans , kep , and ve between groups with and without LVSI were compared using Student's t-test. The receiver operating characteristic (ROC) curve and DeLong test were used to evaluate and compare the diagnostic performance of ECV, Ktrans , kep , and ve for differentiating LVSI. P < 0.05 was considered statistically significant. RESULTS: The ECV and Ktrans of the LVSI group were significantly higher than that of non-LVSI group (52.86% vs. 36.77%, 0.239 vs. 0.176, respectively), and no significant differences in Kep or ve values were observed (P = 0.071 and P = 0.168, respectively). The ECV fraction showed significantly higher area under ROC curve than Ktrans for differentiating LVSI (0.874 vs. 0.655, respectively). DATA CONCLUSION: ECV measurements based on T1 mapping might improve the discrimination between patients with and without LVSI in cervical cancer, showing better performance for this purpose than DCE-MRI. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Causal relationship between the blood immune cells and intervertebral disc degeneration: univariable, bidirectional and multivariable Mendelian randomization.

Background: Intervertebral disc degeneration (IVDD) is a prominent contributor to chronic low back pain, impacting millions of individuals annually. Current research on disc degeneration is placing a growing emphasis on the role of the immune system in this process. Nevertheless, the precise relationship between immunity and disc degeneration remains to be fully elucidated. Method: We obtained GWAS data for immune cells from the latest summary-level GWAS, including 6,620 individuals from Sardinian and 746,667 individuals from five global populations. Summary results for IVDD were sourced from the FinnGen consortium, comprising 20,001 cases and 164,682 controls. We conducted a comprehensive univariable Mendelian randomization (MR) analysis to explore the potential causal relationship between immune cells and IVDD. Primary estimation was carried out using Inverse-Variance Weighting (IVW). To ensure robustness, we employed additional MR methods such as MR-Egger, Weighted Median, Weighted Mode, and Simple Mode. Various tests were employed to assess pleiotropy and heterogeneity, including the Cochran Q test, leave-one-out test, MR-Egger intercept analysis and MR-PRESSO test. To account for potential confounding factors among the immune cells, we conducted a multivariable MR analysis. Finally, we investigated the possibility of a reverse association between immune cells and IVDD through bidirectional MR. Result: In total, our study identified 15 immune cells significantly associated with IVDD through univariable MR. Among these, 9 immune cell types were indicated as potential contributors to IVDD, while 6 were found to have protective effects. Importantly, we observed no evidence of heterogeneity or pleiotropy, signifying the robustness of our results. To mitigate confounding among immune cells, we utilized multivariable MR, leading to the discovery that only 9 immune cell types exerted independent effects on IVDD. These encompassed 7 as risk factors and 2 as protective factors. Additionally, our analysis revealed a bidirectional causal relationship between CD39+ CD4+ T cell %CD4+ T cell and IVDD. Conclusion: Our findings suggest a connection between immune cells and the risk of IVDD, shedding light on potential therapeutic avenues for modulating immune cell function in individuals with IVDD. However, the specific underlying mechanisms warrant further investigation in future experiments.

Effects of Chitosan Oligosaccharide on Production Performance, Egg Quality and Ovarian Function in Laying Hens with Fatty Liver Syndrome.

This study aimed to investigate the role of chitosan oligosaccharide (COS) as an additive in the feed of laying hens with fatty liver syndrome (FLS). Effects on production performance, egg quality as well as ovarian function were determined. A total of 360 Lohmann Pink-shell laying hens (28 weeks old) were randomly assigned to 5 groups (6 replicates × 12 birds). Hens were fed with a basal diet and a high-energy low-protein (HELP) diet supplemented with 0, 200, 400 and 800 mg/kg COS. COS reversed the lowered laying rates, increased feed-to-egg ratios and decreased albumen heights and Haugh units induced by the HELP diet. Additionally, COS improved the ovarian morphologies damaged by the HELP diet. Furthermore, COS enhanced antioxidant enzyme activities, reduced malonaldehyde levels and downregulated the mRNA expressions of nuclear factor kappa B, pro-inflammation cytokine genes and pro-apoptosis-related genes, while it upregulated the mRNA expression of anti-apoptosis-related genes in the ovaries of HELP-diet-fed hens. These findings suggested that dietary COS supplementation could improve production performance and egg quality in laying hens with FLS, and these beneficial effects were linked to improved ovarian morphology, which was attributed to decreased oxidative stress, inflammation and apoptosis in the ovaries.

Low-Temperature UVO-Sintered ZnO/SnO2 as Robust Cathode Buffer Layer for Ternary Organic Solar Cells.

The cathode buffer layer (CBL) plays a crucial role in organic solar cells (OSCs), and it has been challenging to obtain high-quality CBL by using simple and reliable processes. In this paper, the bilayer structure consisting of ZnO nanoparticles (NPs) and sol−gel SnO2 was prepared by the low-temperature (<100 °C) UV-ozone (UVO) sintering process and used as the robust CBL for ternary OSCs based on PTB7-Th:PCDTBT:PC70BM. The results show that the insertion of SnO2 can effectively fill the cracks and pores on the surface of the ZnO NP film, thereby improving the overall compactness and flatness of the CBL and reducing the defect density inside the CBL. Furthermore, the insertion of SnO2 slightly improves the transmittance of the CBL to photons with wavelengths in the range of 400−600 nm, and also increases the electron mobility of the CBL thus facilitating the extraction and transport of the electrons. Compared to the devices using UVO-ZnO and UVO-SnO2 CBLs, the devices with UVO-ZnO/SnO2 CBL exhibit exceptional performance advantages, the best power conversion efficiency (PCE) reaches 10.56%. More importantly, the stability of the devices with ZnO/SnO2 CBL is significantly improved, the device (PCE) still maintains 60% of the initial value after 30 days in air. The positive results show that the UVO-ZnO/SnO2 is an ideal CBL for OSCs, and due to the low-temperature process, it has great application potential in flexible OSCs.

Effect of Controlling Nutritional Status Score (CONUT) and Prognostic Nutritional Index (PNI) on patients after spinal tuberculosis surgery.

The controlling nutritional status (CONUT) score and prognostic nutrition index (PNI) are immune-nutritional biomarkers that are related to clinical prognosis. Previous studies have reported using them to predict the prognosis of traumatic brain injury, tumours and other diseases. The purpose of this study was to evaluate the relationship between the PNI and CONUT score and the one-year prognosis of patients with spinal tuberculosis (STB). In this study, the clinical characteristics of 97 patients with STB who underwent debridement and internal fixation at our institution between 2015 and 2020 were retrospectively analysed. According to the receiver operating characteristic (ROC) curve, patients were divided into two groups: a high CONUT group and a low CONUT group. Patients were also divided into a high PNI group and a low PNI group. One-year postoperative prognosis was evaluated by the clinical cure standard. Patients in the favourable group were younger and had a lower rate of pneumonia and urinary tract infection, higher PNI and lower CONUT score than those in the favourable group (P < 0.05). There was an obvious correlation between the PNI and CONUT score (r = - 0.884, P < 0.05). The areas under the curve (AUCs) of the CONUT score and PNI for predicting unfavourable prognosis were 0.888 (95% CI 0.808-0.943, P < 0.001) and 0.896 (95% CI 0.818-0.949, P < 0.001), respectively. The adjusted odds ratios (ORs) of the CONUT score and PNI for predicting unfavourable outcomes were 2.447 (95% CI 1.518-4.043, P < 0.001) and 0.689 (95% CI 0.563-0.843, P < 0.001), respectively. Higher CONUT scores and a lower PNI were associated with adverse outcomes in patients with spinal tuberculosis, and the CONUT score and PNI might be independent predictors of adverse outcomes of spinal tuberculosis postoperatively.

An improved method for rapid identification of hook effect samples in HBsAg quantitative assay.

Quantitative hepatitis B surface antigen assay is widely used for diagnosis of hepatitis B virus infection; however, specimens with high levels of the antigen can cause false-negative results (Hook effect), which needs to be resolved. The hook effect samples and non-hook effect samples were detected on the LiCA® 500 instrument using three methods, viz., 1, 2, and 3. Method 1, the currently used procedure, was performed in two steps with a total reaction time of 25 min in a final volume of 250 µL: first incubation was with two reagents for 15 min and then with one other reagent for 10 min. In Method 2, all three reagents were added in one step with a final volume of 250 µL, and the total reaction time was still 25 min. In Method 3, the improved method, all three reagents were added in one step while the final volume was only 130 µL and the total reaction time was only 1 min. Signal values of the non-hook effect samples obtained using Method 2 were significantly lower than those with Method 1, showing competitive inhibition. The hook effect samples tested with Method 2 approximated those obtained using Method 1. Method 3 took 1 min and differentiated hook effect samples successfully, similar to the results with Method 2 which took 25 min. Changing the timing of one reagent addition and incubation time in Method 3 provided a rapid and effective method for the identification of hook effect. The results were more clearly distinguishable due to the phenomenon of competitive inhibition. Method 3 can be considered an improvement on the chemiluminescence platform.

An Integration of MicroRNA and Transcriptome Sequencing Analysis Reveal Regulatory Roles of miRNAs in Response to Chilling Stress in Wild Rice.

A chromosome single segment substitution line (CSSL) DC90, which was generated by introgressing CTS-12, a locus derived from common wild rice (Oryza rufipogon Griff.), into the 9311 (Oryza sativa L. ssp. indica) background, exhibits a chilling tolerance phenotype under chilling stress. Here, an integration of microRNA (miRNA) deep sequencing and transcriptomic sequencing analysis was performed to explore the expression profiles of miRNAs and their target genes mediated by CTS-12 under chilling stress, and to reveal the possible regulatory mechanisms of miRNAs that are involved in chilling tolerance. Integration analysis revealed that a number of differentially expressed miRNAs (DEMs) and putative target genes with different expression patterns and levels were identified in 9311 and DC90 under chilling stress. KEGG enrichment analysis revealed that the target genes that are regulated by chilling-induced miRNAs are involved in the regulation of various biological processes/pathways, including protein biosynthesis, redox process, photosynthetic process, and chloroplast development in two genotypes. CRISPR/Cas9 editing of the target genes of the key DEMs in a chilling tolerant rice variety Zhonghua 11 (ZH11) found that LOC_Os11g48020 (OsGL1-11), one of the putative target genes of osa-miR1846a/b-5p and encoding a wax synthesis protein, is correlated with a chilling stress tolerance phenotype, implying osa-miR1846a/b-5p/OsGL1-11 plays an important role in CTS-12-mediated chilling stress tolerance regulatory pathway(s). Therefore, we speculate that the CTS-12 may regulate the key miRNA target genes in response to chilling stress by differential regulation of miRNAs in wild rice, thereby resulting in the variation of chilling tolerance phenotype between 9311 and DC90.

An orally available Mpro inhibitor is effective against wild-type SARS-CoV-2 and variants including Omicron.

Emerging SARS-CoV-2 variants continue to cause waves of new infections globally. Developing effective antivirals against SARS-CoV-2 and its variants is an urgent task. The main protease (Mpro) of SARS-CoV-2 is an attractive drug target because of its central role in viral replication and its conservation among variants. We herein report a series of potent α-ketoamide-containing Mpro inhibitors obtained using the Ugi four-component reaction. The prioritized compound, Y180, showed an IC50 of 8.1 nM against SARS-CoV-2 Mpro and had oral bioavailability of 92.9%, 31.9% and 85.7% in mice, rats and dogs, respectively. Y180 protected against wild-type SARS-CoV-2, B.1.1.7 (Alpha), B.1.617.1 (Kappa) and P.3 (Theta), with EC50 of 11.4, 20.3, 34.4 and 23.7 nM, respectively. Oral treatment with Y180 displayed a remarkable antiviral potency and substantially ameliorated the virus-induced tissue damage in both nasal turbinate and lung of B.1.1.7-infected K18-human ACE2 (K18-hACE2) transgenic mice. Therapeutic treatment with Y180 improved the survival of mice from 0 to 44.4% (P = 0.0086) upon B.1.617.1 infection in the lethal infection model. Importantly, Y180 was also highly effective against the B.1.1.529 (Omicron) variant both in vitro and in vivo. Overall, our study provides a promising lead compound for oral drug development against SARS-CoV-2.

Impact of Upper Airway Characteristics on Disease Severity and CPAP Therapy in Chinese Patients With OSA: An Observational Retrospective Study.

Objective: The characteristics of the upper airway (UA) are important for the evaluation and treatment of obstructive sleep apnea (OSA). This study aimed to investigate the association of UA characteristics with OSA severity, titration pressure, and initiation of and 3-month compliance with continuous positive airway pressure (CPAP). Methods: This retrospective study included consecutive patients examined using a semi-quantitative UA evaluation system (combination with physical examination and awake endoscopy) during 2008-2018 at the Department of Respiratory and Critical Care Medicine, Peking University First Hospital. First, the differences in UA characteristics were compared between patients with simple snorers and mild OSA and those with moderate-to-severe OSA. Then, the effect of UA characteristics on the initiation to CPAP therapy and 3-month adherence to CPAP was conducted. Results: Overall, 1,002 patients were included, including 276 simple snorers and patients in the mild OSA group [apnea-hypopnea index (AHI) <15] and 726 patients in the moderate-to-severe OSA group (AHI ≥15). Tongue base hypertrophy, tonsillar hypertrophy, mandibular recession, neck circumstance, and body mass index (BMI) were independent risk factors for moderate-to-severe OSA. Among those patients, 119 patients underwent CPAP titration in the sleep lab. The CPAP pressures in patients with thick and long uvulas, tonsillar hypertrophy, lateral pharyngeal wall stenosis, and tongue hypertrophy were higher than those of the control group (P < 0.05, respectively). The logistic regression analysis showed that nasal turbinate hypertrophy, mandibular retrusion, and positive Müller maneuver in the retropalate and retroglottal regions were independent predictors for the initiation of home CPAP treatment. Conclusion: Multisite narrowing and function collapse of the UA are important factors affecting OSA severity, CPAP titration pressure, and the initiation of home CPAP therapy. Clinical evaluation with awake endoscopy is a safe and effective way for the assessment of patients with OSA in internal medicine.

Viral resistance to VRC01-like antibodies with mutations in loop D and V5 from an HIV-1 B' subtype infected individual with broadly neutralization activity.

Recently we identified the VRC01-like antibody DRVIA7(A7) from an HIV-1 B' subtype-infected individual (DRVI01) with broad neutralization activity, and almost all viruses from the individual were resistant to both VRC01 and A7 lineage antibodies. Here, we identified and characterized a panel of HIV-1 variants with resistance to VRC01 and A7 using site-directed mutagenesis and swapping amino acid fragments of gp120. Site-directed mutagenesis revealed that E279D/R282K/N460A/T464N of gp120 from DRVI01 produced VRC01-susceptible variants. Multiple mutations significantly increased the neutralization sensitivity to VRC01. Residues N464 located at the tip of the V5 loop were considered irrelevant to the neutralization of VRC01. For DRVI01-derived viruses, the single N464T change fully produced VRC01-resistant variants; conversely, a single T464N mutation generated VRC01-susceptible variants. Alanine scanning revealed that the N464 residue plays a vital role in binding with VRC01. Neutralizing assays against A7 lineage antibodies showed that DRVI01-derived viruses with multiple mutations could be neutralized by A7 lineage antibodies with different neutralizing breadths. Combining the changes in loops D and V5 produced variants that were totally sensitive variants to A7 lineage antibodies.

Maternal magnolol supplementation alters placental morphology, promotes placental angiogenesis during mid-gestation and improves offspring growth in a pregnant mouse model.

The placenta is the organ that determines the growth of the fetus and the outcome of pregnancy. Magnolol is a multifunctional polyphenol with antioxidant, anti-inflammatory, anticancer and neuroprotective functions. However, there is less knowledge of the effects or complications in the placenta and the mechanism underlying the effect of magnolol when used during pregnancy. The aim of this study was to explore the effects of maternal magnolol supplementation on pregnancy outcomes and placental alterations in a pregnant mouse model. A total of 128 pregnant mice were randomly divided into 4 groups supplemented with 0, 40, 80 and 160 µM magnolol from gestational day 0 (GD0) to delivery. Our results revealed that the number of large-for-gestation-age fetuses on GD13 and the weaning weight of offspring were increased in the magnolol treatment groups. Moreover, maternal magnolol supplementation increased superoxide dismutase (SOD), decreased malondialdehyde (MDA) in maternal serum, and promoted the expression of heme oxygenase-1 (HO-1) in the placenta. Furthermore, magnolol significantly increased the area of the junctional zone and decidua in the placentas and increased the expression of interferon-γ (INF-γ), tumor necrosis factor-α (TNF-α), chemokine (CC Motif) Ligand 3 (CCL3), chemokine (CXC motif) ligand 10 (CXCL10), insulin-like growth factor-1 (IGF-1) and T-box transcription factor 21 (T-bet) in the placenta during GD13 in pregnant mice, while suppressor of cytokine signaling 1 (SOCS1) was reduced. Moreover, the ratio of blood space in the labyrinth area, hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) were all increased in the magnolol treatment groups on GD13. Taken together, these results indicate that magnolol can improve the growth of offspring, which might be due to the alteration of placental morphology and the promotion of placental angiogenesis during mid-gestation.