Oncological risk of proximal gastrectomy for proximal advanced gastric cancer after neoadjuvant chemotherapy.

PURPOSE: This study assesses the metastasis rate of the key distal lymph nodes (KDLN) that are not routinely dissected in proximal gastrectomy, aiming to explore the oncological safety of proximal gastrectomy for upper gastric cancer who underwent neoadjuvant chemotherapy. METHODS: We analyzed a cohort of 150 patients with proximal locally advanced gastric cancer (cT3/4 before chemotherapy) from two high-volume cancer centers in China who received preoperative neoadjuvant chemotherapy (NAC) and total gastrectomy with lymph node dissection. Metastasis rate of the KDLN (No.5/6/12a) and the risk factors were analyzed. RESULTS: Key distal lymph node metastasis was detected in 10% (15/150) of patients, with a metastasis rate of 6% (9/150) in No. 5 lymph nodes, 6.7% (10/150) in No. 6 lymph nodes, and 2.7% (2/75) in No. 12a lymph nodes. The therapeutic value index of KDLN as one entity is 5.8. Tumor length showed no correlation with KDLN metastasis, while tumor regression grade (TRG) emerged as an independent risk factor (OR: 1.47; p-value: 0.04). Of those with TRG3 (no response to NAC), 80% (12/15) was found with KDLN metastasis. CONCLUSION: For cT3/4 proximal locally advanced gastric cancer patients, the risk of KDLN metastasis remains notably high even after NAC. Therefore, proximal gastrectomy is not recommended; instead, total gastrectomy with thorough distal lymphadenectomy is the preferred surgical approach.

BTLA contributes to acute-on-chronic liver failure infection and mortality through CD4+ T-cell exhaustion.

B- and T-lymphocyte attenuator (BTLA) levels are increased in patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). This condition is characterized by susceptibility to infection and T-cell immune exhaustion. However, whether BTLA can induce T-cell immune exhaustion and increase the risk of infection remains unclear. Here, we report that BTLA levels are significantly increased in the circulating and intrahepatic CD4+ T cells from patients with HBV-ACLF, and are positively correlated with disease severity, prognosis, and infection complications. BTLA levels were upregulated by the IL-6 and TNF signaling pathways. Antibody crosslinking of BTLA activated the PI3K-Akt pathway to inhibit the activation, proliferation, and cytokine production of CD4+ T cells while promoting their apoptosis. In contrast, BTLA knockdown promoted their activation and proliferation. BTLA-/- ACLF mice exhibited increased cytokine secretion, and reduced mortality and bacterial burden. The administration of a neutralizing anti-BTLA antibody reduced Klebsiella pneumoniae load and mortality in mice with ACLF. These data may help elucidate HBV-ACLF pathogenesis and aid in identifying novel drug targets.

Intrahepatic homeobox protein MSX-1 is a novel host restriction factor of hepatitis B virus.

Chronic hepatitis B virus (HBV) infection (CHB) is a risk factor for the development of liver fibrosis, cirrhosis, and hepatocellular carcinoma. Covalently closed circular DNA serves as the sole transcription template for all viral RNAs and viral transcription is driven and enhanced by viral promoter and enhancer elements, respectively. Interactions between transcription factors and these cis-elements regulate their activities and change the production levels of viral RNAs. Here, we report the identification of homeobox protein MSX-1 (MSX1) as a novel host restriction factor of HBV in liver. In both HBV-transfected and HBV-infected cells, MSX1 suppresses viral gene expression and genome replication. Mechanistically, MSX1 downregulates enhancer II/core promoter (EnII/Cp) activity via direct binding to an MSX1 responsive element within EnII/Cp, and such binding competes with hepatocyte nuclear factor 4α binding to EnII/Cp due to partial overlap between their respective binding sites. Furthermore, CHB patients in immune active phase express higher levels of intrahepatic MSX1 but relatively lower levels of serum and intrahepatic HBV markers compared to those in immune tolerant phase. Finally, MSX1 was demonstrated to induce viral clearance in two mouse models of HBV persistence, suggesting possible therapeutic potential for CHB.IMPORTANCECovalently closed circular DNA plays a key role for the persistence of hepatitis B virus (HBV) since it serves as the template for viral transcription. Identification of transcription factors that regulate HBV transcription not only provides insights into molecular mechanisms of viral life cycle regulation but may also provide potential antiviral targets. In this work, we identified host MSX1 as a novel restriction factor of HBV transcription. Meanwhile, we observed higher intrahepatic MSX1 expression in chronic hepatitis B virus (CHB) patients in immune active phase compared to those in immune tolerant phase, suggesting possible involvement of MSX1 in the regulation of HBV activity by the host. Lastly, intrahepatic overexpression of MSX1 delivered by recombinant adenoviruses into two mouse models of HBV persistence demonstrated MSX1-mediated repression of HBV in vivo, and MSX1-induced clearance of intrahepatic HBV DNA in treated mice suggested its potential as a therapeutic target for the treatment of CHB.

Immunomodulation of cuproptosis and ferroptosis in liver cancer.

According to statistics, the incidence of liver cancer is increasing yearly, and effective treatment of liver cancer is imminent. For early liver cancer, resection surgery is currently the most effective treatment. However, resection does not treat the disease in advanced patients, so finding a method with a better prognosis is necessary. In recent years, ferroptosis and cuproptosis have been gradually defined, and related studies have proved that they show excellent results in the therapy of liver cancer. Cuproptosis is a new form of cell death, and the use of cuproptosis combined with ferroptosis to inhibit the production of hepatocellular carcinoma cells has good development prospects and is worthy of in-depth discussion by researchers. In this review, we summarize the research progress on cuproptosis combined with ferroptosis in treating liver cancer, analyze the value of cuproptosis and ferroptosis in the immune of liver cancer, and propose potential pathways in oncotherapy with the combination of cuproptosis and ferroptosis, which can provide background knowledge for subsequent related research.

A novel synthetic method for backbone-cyclized polypeptide POL7080 with the help of hydrophobic-support materials.

Murepavadin (POL7080) in phase III clinical trials, a backbone-cyclized polypeptide composed of 14 amino acids, has a novel mode of action and shows a specific and efficient bactericidal effect against multidrug-resistant Pseudomonas aeruginosa. It is a potential candidate to treat severe P. aeruginosa infections in the future and still has significant commercial value for further research and development. In this paper, we report a liquid-phase peptide synthetic route for this valuable candidate polypeptide assisted by hydrophobic-support materials (tags), which overcomes the difficulties of high cost and poor yield in the traditional solid-phase synthesis of macrocyclic peptides. Through the careful optimization of reaction conditions and the innovative strategy of synthetic post-treatment, we established a simple and efficient liquid-phase synthetic route suitable for POL7080 and other similar structures, with satisfactory yield, high purity and a production process not being controlled by scale.

A novel screening method of DNA methylation biomarkers helps to improve the detection of colorectal cancer and precancerous lesions.

BACKGROUND: Colorectal cancer (CRC) is one of the most common malignancies, and early detection plays a crucial role in enhancing curative outcomes. While colonoscopy is considered the gold standard for CRC diagnosis, noninvasive screening methods of DNA methylation biomarkers can improve the early detection of CRC and precancerous lesions. METHODS: Bioinformatics and machine learning methods were used to evaluate CRC-related genes within the TCGA database. By identifying the overlapped genes, potential biomarkers were selected for further validation. Methylation-specific PCR (MSP) was utilized to identify the associated genes as biomarkers. Subsequently, a real-time PCR assay for detecting the presence of neoplasia or cancer of the colon or rectum was established. This screening approach involved the recruitment of 978 participants from five cohorts. RESULTS: The genes with the highest specificity and sensitivity were Septin9, AXL4, and SDC2. A total of 940 participants were involved in the establishment of the final PCR system and the subsequent performance evaluation test. A multiplex TaqMan real-time PCR system has been illustrated to greatly enhance the ability to detect precancerous lesions and achieved an accuracy of 87.8% (95% CI 82.9-91.5), a sensitivity of 82.7% (95% CI 71.8-90.1), and a specificity of 90.1% (95% CI 84.3-93.9). Moreover, the detection rate of precancerous lesions of this assay reached 55.0% (95% CI 38.7-70.4). CONCLUSION: The combined detection of the methylation status of SEPT9, SDC2, and ALX4 in plasma holds the potential to further enhance the sensitivity of CRC detection.

[Retracted] Long non­coding RNA RNCR3 promotes glioma progression involving the Akt/GSK­3ß pathway.

[This retracts the article DOI: 10.3892/ol.2019.11002.].

In-hospital adverse outcomes and risk factors among chronic kidney disease patients infected with the omicron variant of SARS-CoV-2: a single-center retrospective study.

INTRODUCTION: The SARS-CoV-2 Omicron variant has decreased virulence and pathogenicity, yet the number of Omicron infections worldwide is unprecedentedly high, with rather high mortality and severe disease rate. Chronic kidney disease (CKD) patients are particularly vulnerable to the SARS-CoV-2 Omicron variant and have unique clinical outcomes. METHODS: We retrospectively collected data from 2140 hospitalized patients with SARS-CoV-2 Omicron variant infection from March 29, 2022, to May 17, 2022. Demographic characteristics, ancillary examination results, and clinical treatments were described. Occurrence of critical COVID-19 or death and time of positive-to-negative conversion was defined as primary outcomes. The presence of COVID-19 pneumonia and the usage of respiratory or circulatory support was defined as secondary outcomes. Univariate or multivariate logistic regression analyses were performed to identify risk factors for primary outcomes. RESULTS: 15.74% of CKD patients infected with the SARS-CoV-2 Omicron variant ended up with critical COVID-19 or death. Pre-existing CKD was a risk factor for critical COVID-19 or death and prolonged time of positive-to-negative conversion of SARS-CoV-2. Nirmatrelvir-ritonavir facilitated viral clearance among COVID-19 patients with non-severe CKD. CONCLUSION: We found patients with CKD and COVID-19 due to Omicron experienced worse clinical outcomes and prolonged time of positive-to-negative conversion of SARS-CoV-2 compared to patients without CKD, which helps rationalize limited medical resources and offers guidance for appropriate clinical treatments.

Harmonization of distributed multi-center analysis based on dried blood spot reference materials supporting the screening of neonatal inherited metabolic disorders.

BACKGROUND: The standardization of quantification data is critical for ensuring the reliability and measurement traceability in the screening of neonatal inherited metabolic disorders. However, the availability of national certified reference materials is limited in China. METHODS: In this study, we developed a series of dried blood spot (DBS) reference materials containing 9 amino acids (AA) and 10 acylcarnitines (AC) for neonatal screening. Four levels of the reference materials were measured with tandem mass spectrometry (MS/MS) by seven laboratories using different commercial In Vitro Diagnostic Device (IVD) kits. Then, 100 clinical samples were measured using both derivatization and non-derivatization methods by the same laboratory. RESULTS: We found high homogeneity and stability at all levels of the reference materials, with the coefficient of variation (CV) of the analytes less than 15%. These reference materials can be used to assess the testing capabilities of different laboratories. Our test also revealed that the correction factors (CF) calculated by the reference materials, along with clinical samples, could increase the consistency for different kits. CONCLUSION: The DBS reference materials proposed in this study provide reliability for the harmonization in multi-center analysis for the screening of neonatal inherited metabolic disorders. And applying our correction method for the screening could improve the data consistency of the DBS samples prepared by different methods.

Lipid nanoparticle-mediated delivery of IL-21-encoding mRNA induces viral clearance in mouse models of hepatitis B virus persistence.

Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA), the transcription template for all viral mRNAs, is highly stable and current treatment options cannot effectively induce its clearance. Previously, we established an HBV persistence mouse model based on a clinical isolate (termed BPS) and identified interleukin-21 (IL-21) as a potent inducer of HBV clearance. Lipid nanoparticle (LNP) mediated delivery of mRNA has proven to be a highly safe and effective delivery platform. This work explored the applicability and effectiveness of the mRNA-LNP platform in IL-21-based HBV therapies. First, LNP-encapsulated murine IL-21 mRNA (LNP-IL-21) was prepared, characterized, and demonstrated to engender IL-21 expression in vitro and in vivo. Next, LNP-IL-21 was shown to induce clearance of both serum and intrahepatic HBV antigen and DNA in two HBV persistence mouse models based on BPS and recombinant cccDNA (rcccDNA), respectively, which was associated with HBV-specific humoral and cellular immune responses. Furthermore, peripheral blood mononuclear cells from BPS persistence mice treated ex vivo with LNP-IL-21 and HBV surface antigen (HBsAg) could induce similar HBV clearance upon infusion into recipient mice. These findings indicated that IL-21 combined with mRNA-LNP platform represents a valid and promising strategy for developing novel therapeutics against chronic HBV infection.

A sensitive mass spectrometry-based method to identify common respiratory pathogens in children.

Public health threats posed by emerging respiratory infections are a significant concern, particularly in children and infants. Traditional culture-based detection methods are time-consuming and typically require 1-3 days. Herein, we developed and evaluated a 23-plex common respiratory pathogen mass spectrometry assay that enables the simultaneous detection of 18 common respiratory pathogens in children. This assay combines matrix-assisted laser desorption/ionization time of flight mass spectrometry with multiplex reverse transcription-PCR and targets 11 bacterial and 7 viral pathogens (including 10 subtypes), and two internal controls. The detection limit of the common respiratory pathogen mass spectrometry assay was as low as 1 copy/µL, with no cross-reactivity with other organisms. We assessed the clinical performance of the common respiratory pathogen mass spectrometry assay using respiratory samples from 450 children. The total 450 clinical specimens underwent analysis via matrix-assisted laser desorption/ionization time of flight mass spectrometry, and the outcomes were juxtaposed with those derived from real-time reverse-transcriptase PCR conducted concurrently. The concordance between these methods was 96.0%, and the multiple infection identification rate was 7.1%. This innovative approach enables the simultaneous analysis of numerous outcomes from a solitary examination across 192 specimens within a timeframe of approximately 7 hours, with a dramatically reduced sample use and cost. In summary, the common respiratory pathogen mass spectrometry assay is a sensitive, accurate, and cost-effective method for detecting common respiratory pathogens in children and has the potential to revolutionize the diagnosis of respiratory tract infections. IMPORTANCE This study aimed to present and evaluate a novel co-detection method that enables the simultaneous identification of 11 bacterial and 7 viral pathogens in about 7 hours using matrix-assisted laser desorption/ionization time of flight mass spectrometry. Our approach utilizes a combination of multiplex reverse transcription-PCR and matrix-assisted laser desorption/ionization time of flight mass spectrometry, which overcomes the limitations of conventional assays, which include a long assessment time, technical difficulty, and high costs. As a screening method for common respiratory pathogens in children, common respiratory pathogen mass spectrometry assay has the potential to revolutionize the diagnosis of respiratory tract infections by providing an accurate etiological diagnosis. The common respiratory pathogen mass spectrometry assay is expected to be a critical tool for the diagnosis of respiratory infections in children, offering a more efficient, cost-effective, and accurate approach for the detection of common respiratory pathogens.

Desmoplastic Reaction Associates with Prognosis and Adjuvant Chemotherapy Response in Colorectal Cancer: A Multicenter Retrospective Study.

Desmoplastic reaction (DR) is one of many tumor-host interactions and is associated with the overall survival (OS) of patients with colorectal cancer. However, the clinical significance of DR requires further study in large multicenter cohorts and its predictive value in adjuvant chemotherapy (ACT) response remains unclear. Here, a total of 2,225 patients with colorectal cancer from five independent institutions were divided into primary (N = 1,012 from two centers) and validation (N = 1,213 from three centers) cohorts. DR was classified as immature, middle, or mature depending on the presence of myxoid stroma and hyalinized collagen bundles at the invasive front of the primary tumor. OS among different subgroups were compared, and the correlations of DR type with tumor-infiltrating lymphocytes (TILs) within stroma, tumor stroma ratio (TSR), and Stroma AReactive Invasion Front Areas (SARIFA) were also analyzed. In the primary cohort, patients with mature DR had the highest 5-year survival rate. These findings were confirmed in validation cohort. In addition, for stage II colorectal cancer, patients classified as non-mature DR would benefit from ACT compared with surgery alone. Furthermore, immature and middle DR were more associated with high TSR, less distribution of TILs within stroma and positive SARIFA compared with mature. Taken together, these data suggest that DR is a robust-independent prognostic factor for patients with colorectal cancer. For patients with stage II colorectal cancer, non-mature DR could be a potential marker for recognizing high-risk patients who may benefit from ACT. Significance: DR has the potential to identify patients with high-risk colorectal cancer and predict the efficacy of adjuvant chemotherapy in patients with stage II colorectal cancer. Our findings support reporting DR types as additional pathologic parameters in clinical practice for more precise risk stratification.

Design and Synthesis of 4-Fluorophenyl-5-methylene-2(5H)-furanone Derivatives as Potent Quorum Sensing Inhibitors.

Quorum sensing inhibitors (QSIs) are a class of compounds that can reduce the pathogenicity of bacteria without affecting bacterial growth. In this study, we designed and synthesized four series of 4-fluorophenyl-5-methylene-2(5H)-furanone derivatives and evaluated their QSI activities. Among them, compound 23e not only showed excellent inhibitory activity against various virulence factors but also significantly enhanced the inhibitory activity of antibiotics ciprofloxacin and clarithromycin against two strains of Pseudomonas aeruginosa in vitro. What is even more exciting is that it remarkably increased the antibacterial effect in vivo in combination with ciprofloxacin in the bacteremia model infected with P. aeruginosa PAO1. Moreover, 23e had little hemolytic activity to mouse erythrocytes. Further, the results of GFP reporter fluorescence strain inhibition and ß-galactosidase activity inhibition experiments demonstrated that 23e simultaneously targeted the three quorum sensing systems in P. aeruginosa. As a result, compound 23e could be used as an effective QSI for further development against bacterial infections.

Comparison of Pegylated Interferon Alfa Therapy in Combination with Tenofovir Alafenamide Fumarate or Tenofovir Disoproxil Fumarate for Treatment of Chronic Hepatitis B Patients.

Purpose: The study aims to evaluate the effectiveness of a tenofovir alafenamide fumarate (TAF) and pegylated interferon alfa (PegIFN-α) regimen compared to a tenofovir disoproxil fumarate (TDF) and PegIFN-α therapy in patients with chronic hepatitis B (CHB). Patients and Methods: Patients who were treated with PegIFN-α in combination with TAF or TDF were retrospectively enrolled. The primary outcome measured was the HBsAg loss rate. The rates of virological response, serological response for HBeAg, and normalization of alanine aminotransferase (ALT) were also calculated. The cumulative incidences of response rates were compared between the two groups using Kaplan-Meier analysis. Results: A total of 114 patients were retrospectively enrolled in the study, with 33 receiving TAF plus PegIFN-α treatment and 81 receiving TDF plus PegIFN-α treatment. The HBsAg loss rate for the TAF plus PegIFN-α group was 15.2% at 24 weeks and 21.2% at 48 weeks, while the TDF plus PegIFN-α group had rates of 7.4% at 24 weeks and 12.3% at 48 weeks (P=0.204 at 24 weeks, P=0.228 at 48 weeks). In subgroup analysis of HBeAg positive patients, the TAF group had a higher HBsAg loss rate of 25% at week 48, compared to 3.8% in the TDF group (P=0.033). According to Kaplan-Meier analysis, the TAF plus PegIFN-α group achieved virological response more quickly than the TDF plus PegIFN-α group (p=0.013). There was no statistical difference in HBeAg serological rate or ALT normalization rate. Conclusion: There was no significant difference in the HBsAg loss between the two groups. However, subgroup analysis revealed that TAF plus PegIFN-α treatment had a higher HBsAg loss rate than TDF plus PegIFN-α treatment in HBeAg-positive patients. Additionally, TAF plus PegIFN-α treatment demonstrated better virological suppression for CHB patients. Therefore, TAF plus PegIFN-α treatment regimen is recommended for CHB patients who aim to achieve functional cure.

Design, synthesis and evaluation of oxazolopyridinone derivatives as quorum sensing inhibitors.

The antibiotic crisis is associated with the appearance of multidrug resistant (MDR) pathogens, which has caused severe bacterial infections and imposed a huge burden on modern society. Therefore, there is an urgent need to develop new antibacterial drugs with novel mechanism of action. Here we designed and synthesized three series of benzoxazolone, oxazolopyridinone and 3-(2-hydroxyphenyl)hydantoin derivatives and evaluated their activity as novel quorum sensing (QS) inhibitors. We found that benzoxazolone and oxazolopyridinone derivatives had promising QS inhibitory activity in the minimum inhibitory concentration, pyocyanin and rhamnolipid inhibition assays. In particular, A10 and B20 at 256 µg/mL not only suppressed pyocyanin production regulated by QS in P. aeruginosa PAO1 by 36.55% and 46.90%, respectively, but also showed the strongest rhamnolipid inhibitory activity with the IC50 values of 66.35 and 56.75 µg/mL, respectively. Further studies demonstrated that B20 at 64 µg/mL inhibited biofilm formation in P. aeruginosa PAO1 by 40%, and weakened its swarming motility. More importantly, the bacterial mortality of B20 combined with ciprofloxacin and clarithromycin against P. aeruginosa were 48.27% and 49.79%, respectively, while ciprofloxacin and clarithromycin had only 16.99% and 29.11% of bacterial mortality against P. aeruginosa when used alone. Mechanistic studies indicated that B20 directly inhibited the QS pathway based on the GFP reporter strain assay. Overall, this compound with oxazolopyridinone core could serve as an antibacterial lead of QS inhibitor for further evaluation of its drug-likeness.

Identification of Estradiol Benzoate as an Inhibitor of HBx Using Inducible Stably Transfected HepG2 Cells Expressing HiBiT Tagged HBx.

HBx plays a significant role in the cccDNA epigenetic modification regulating the hepatitis B virus (HBV) life cycle and in hepatocyte proliferation and carcinogenesis. By using the sleeping-beauty transposon system, we constructed a tetracycline-induced HBx-expressing stable cell line, SBHX21. HBx with a HiBiT tag can be quickly detected utilizing a NanoLuc-based HiBiT detection system. By screening a drug library using SBHX21 cells, we identified estradiol benzoate as a novel anti-HBx agent. Estradiol benzoate also markedly reduced the production of HBeAg, HBsAg, HBV pgRNA, and HBV DNA in a dose-dependent manner, suggesting that estradiol benzoate could be an anti-HBV agent. Docking model results revealed that estradiol benzoate binds to HBx at TRP87 and TRP107. Collectively, our results suggest that estradiol benzoate inhibits the HBx protein and HBV transcription and replication, which may serve as a novel anti-HBV molecular compound for investigating new treatment strategies for HBV infection.

Proportion of asymptomatic infection and nonsevere disease caused by SARS-CoV-2 Omicron variant: A systematic review and analysis.

SARS-CoV-2 Omicron variant seemed to cause milder disease compared to previous predominated variants. We aimed to conduct a meta-analysis to assess the pooled proportion of nonsevere disease and asymptomatic infection among COVID-19 patients infected with Omicron and Delta. We searched PubMed, Embase, Web of Science, and China National Knowledge Infrastructure (CNKI) databases. We included studies of SARS-CoV-2 Omicron infection from November 1, 2021, to April 18, 2022, and studies of Delta infection from October 1, 2020, to June 30, 2022. Studies without corresponding data, with less than 50 patients, or obviously biased concerning main outcome were excluded. Meta-analysis was performed in R 4.2.0 with the "meta" package. Subgroup analyses were conducted by study group and vaccination status. The pooled proportion of asymptomatic infection and nonsevere disease with Omicron were 25.5% (95% confidence interval [CI] 17.0%-38.2%) and 97.9% (95% CI 97.1%-98.7%), significantly higher than those of Delta with 8.4% (95% CI 4.4%-16.2%) and 91.4% (95% CI 87.0%-96.0%). During Omicron wave, children and adolescents had higher proportion of asymptomatic infection, SOTR and the elderly had lower proportion of nonsevere disease, vaccination of a booster dose contributed to higher proportion of both asymptomatic infection and nonsevere disease. This study estimates the pooled proportion of asymptomatic infection and nonsevere disease caused by SARS-CoV-2 Omicron compared to other predominant variants. The result has important implications for future policy making.

SARS-CoV-2 Omicron Variant: Epidemiological Features, Biological Characteristics, and Clinical Significance.

The SARS-CoV-2 Omicron (B.1.1529) variant was designated as a variant of concern (VOC) by the World Health Organization (WHO) on November 26, 2021. Within two months, it had replaced the Delta variant and had become the dominant circulating variant around the world. The Omicron variant possesses an unprecedented number of mutations, especially in the spike protein, which may be influencing its biological and clinical aspects. Preliminary studies have suggested that increased transmissibility and the reduced protective effects of neutralizing antibodies have contributed to the rapid spread of this variant, posing a significant challenge to control the coronavirus disease 2019 (COVID-19) pandemic. There is, however, a silver lining for this wave of the Omicron variant. A lower risk of hospitalization and mortality has been observed in prevailing countries. Booster vaccination also has ameliorated a significant reduction in neutralization. Antiviral drugs are minimally influenced. Moreover, the functions of Fc-mediated and T-cell immunity have been retained to a great extent, both of which play a key role in preventing severe disease.

Exploration of the inhibitory mechanism of PC190723 on FtsZ protein by molecular dynamics simulation.

Bacterial resistance caused by widespread use and abuse of antibiotics is threatening human health, and the development of new antibacterial agents with novel antibacterial targets has become urgent. Filamenting temperature-sensitive mutant Z (FtsZ), as a key protein in bacterial division, has received extensive attention. PC190723 exhibits an outstanding antibacterial activity by producing potent inhibitory ability on FtsZ protein, but its influence on the conformation of FtsZ protein at the molecular level is still unclear. In this study, we explored the effect of PC190723 on the conformation and function of FtsZ protein through molecular dynamics (MD) simulation and post-analysis. The results showed that PC190723 increased the high-affinity conformational stability of FtsZ protein, which disrupts the normal assembly of the Z-ring. In particular, the interactions of residues S8-sheet (VAL260-GLY266) increased in the FtsZPC190723 system, which may be the reason for promotes the formation of protofilament. In brief, the mechanism of PC190723 inhibiting FtsZ protein was explained at the molecular level by MD simulation, which provides new ideas for the identification of new FtsZ inhibitors as antibacterial agents.