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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for coronavirus disease 2019 (COVID-19), has evoked a global pandemic. Due to its rapid transmission rate and the severity of illness, the urgent need for the expedited design and development of effective therapeutics is evident. Computer-aided drug design (CADD) methods have been employed to accelerate the drug development process. More than 30 000 medication compounds were subjected to virtual screening for the SARS-CoV-2 main protease. The top 10 molecules based on the binding affinity scores were chosen and subjected to extra-precision docking and their pharmacokinetic properties were explored to validate whether they bound well to the SARS-CoV-2 main protease. The results indicated that the binding free energy values between Mpro and these ligands predominantly fall within the range of −7 to −8 kcal mol−1, suggesting relatively stable interactions between the ligands and the protein target. Significant contributions to the binding of most small molecules were identified through molecular dynamics simulations and MM/PBSA (molecular mechanics/Poisson–Boltzmann surface area) analyses, with residues such as His164, Glu166, and Asp187 being found to be crucial. Therefore, these residues have been recognized as potential targets for drug design. In summary, ZINC000306568896 exhibited the optimal binding free energy of −28.68 kcal mol−1 and was evaluated as the lead compound with the strongest binding affinity in this series. Its favourable pharmacokinetic properties and its stable association with the active site suggest that it is a promising lead inhibitor for SARS-CoV-2. These results demonstrate that this ligand has great potential to be an ideal lead inhibitor for SARS-CoV-2 and to expedite the development of therapeutic interventions against COVID-19. [ABSTRACT FROM AUTHOR]

BACKGROUND: In China, Tongluo-Qutong rubber plaster (TQRP) is commonly used for cervical spondylotic radiculopathy, but lacks high-quality trials. OBJECTIVE: This study aimed to conduct a multicenter, open-label, parallel-group, randomized controlled trial in China to investigate the practical efficacy and safety of TQRP in the treatment of CSR. METHODS: A total of 240 patients diagnosed with CSR were recruited for the investigation from multiple hospitals in Gansu province, China. The patients were randomly assigned to either an experimental or a control group. The experimental group received treatment with TQRP, whereas the control group was administered a diclofenac sodium patch (DSP) for a maximum duration of 21 days. The visual analogue scale (VAS) score for pain, the proportion of patients experiencing 50% or more pain relief, the neck disability index (NDI), changes as per the Eaton trial, and recurrence during the follow-up period were evaluated for both groups. The safety and adverse events associated with the concurrent drug therapy were also evaluated. RESULTS: At each time point, the mean VAS and NDI scores of both groups demonstrated a downward trend. The experimental group exhibited a greater decline in VAS score at each time point compared to the control group (P < 0.01). In the Eaton trial, both the percentage of patients experiencing pain relief of 50% or more and the number of abnormal results exhibited improvement. However, the outcomes in the 21 ± 3d experimental group were significantly superior to those in the control group (P < 0.01). During the follow-up period, the recurrence events in the experimental group were reduced compared to the control group. The difference between the two groups was statistically significant (P < 0.05). The incidence of adverse reactions was 1.74% for TQRP and 3.54% for DSP. CONCLUSION: TQRP is effective and safe in the treatment of CSR. [ABSTRACT FROM AUTHOR]

Abstract Background Fatty liver is a high incidence of perinatal disease in dairy cows caused by negative energy balance, which seriously threatens the postpartum health and milk production. It has been reported that lysine acetylation plays an important role in substance and energy metabolism. Predictably, most metabolic processes in the liver, as a vital metabolic organ, are subjected to acetylation. Comparative acetylome study were used to quantify the hepatic tissues from the severe fatty liver group and normal group. Combined with bioinformatics analysis, this study provides new insights for the role of acetylation modification in fatty liver disease of dairy cows. Results We identified 1841 differential acetylation sites on 665 proteins. Among of them, 1072 sites on 393 proteins were quantified. Functional enrichment analysis shows that higher acetylated proteins are significantly enriched in energy metabolic pathways, while lower acetylated proteins are significantly enriched in pathways related to immune response, such as drug metabolism and cancer. Among significantly acetylated proteins, many mitochondrial proteins were identified to be interacting with multiple proteins and involving in lipid metabolism. Furthermore, this study identified potential important proteins, such as HADHA, ACAT1, and EHHADH, which may be important regulatory factors through modification of acetylation in the development of fatty liver disease in dairy cows and possible therapeutic targets for NAFLD in human beings. Conclusion This study provided a comprehensive acetylome profile of fatty liver of dairy cows, and revealed important biological pathways associated with protein acetylation occurred in mitochondria, which were involved in the regulation of the pathogenesis of fatty liver disease. Furthermore, potential important proteins, such as HADHA, ACAT1, EHHADH, were predicted to be essential regulators during the pathogenesis of fatty liver disease. The work would contribute to the understanding the pathogenesis of NAFLD, and inspire in the development of new therapeutic strategies for NAFLD.

Background and aims: Liver regeneration retardation post partial hepatectomy (PH) is a common clinical problem after liver transplantation. Identification of key regulators in liver regeneration post PH may be beneficial for clinically improving the prognosis of patients after liver transplantation. This study aimed to clarify the function of junctional protein‐associated with coronary artery disease (JCAD) in liver regeneration post PH and to reveal the underlying mechanisms. Methods: JCAD knockout (JCAD‐KO), liver‐specific JCAD‐KO (Jcad△Hep) mice and their control group were subjected to 70% PH. RNA sequencing was conducted to unravel the related signalling pathways. Primary hepatocytes from KO mice were treated with epidermal growth factor (EGF) to evaluate DNA replication. Fluorescent ubiquitination‐based cell cycle indicator (FUCCI) live‐imaging system was used to visualise the phases of cell cycle. Results: Both global and liver‐specific JCAD deficiency postponed liver regeneration after PH as indicated by reduced gene expression of cell cycle transition and DNA replication. Prolonged retention in G1 phase and failure to transition over the cell cycle checkpoint in JCAD‐KO cell line was indicated by a FUCCI live‐imaging system as well as pharmacologic blockage. JCAD replenishment by adenovirus reversed the impaired DNA synthesis in JCAD‐KO primary hepatocyte in exposure to EGF, which was abrogated by a Yes‐associated protein (YAP) inhibitor, verteporfin. Mechanistically, JCAD competed with large tumour suppressor 2 (LATS2) for WWC1 interaction, leading to LATS2 inhibition and thereafter YAP activation, and enhanced expression of cell cycle‐associated genes. Conclusion: JCAD deficiency led to delayed regeneration after PH as a result of blockage in cell cycle progression through the Hippo–YAP signalling pathway. These findings uncovered novel functions of JCAD and suggested a potential strategy for improving graft growth and function post liver transplantation. Key Points: JCAD deficiency leads to an impaired liver growth after PH due to cell division blockage.JCAD competes with LATS2 for WWC1 interaction, resulting in LATS2 inhibition, YAP activation and enhanced expression of cell cycle‐associated genes.Delineation of JCADHippoYAP signalling pathway would facilitate to improve prognosis of acute liver failure and graft growth in living‐donor liver transplantation. [ABSTRACT FROM AUTHOR]

In forensic science practice, age is an important individual information, and one of the indicators to be considered first to depict features of the suspect. Recently, DNA methylation has become a research hotspot in age estimation because of its hig accuracy and stability. New progress has been made in specificity of DNA methylation sites, age estimation in multiple tissues, DNA methylation age estimation of minors, sensitivity of age estimation, forensic practical applications, etc. At the same time, several studies also established more accurate statistical modeling methods, eliminated differences between different detection platforms, found appropriate number of sites in models and analyzed the influence of environment and diseases. This review summarizes these to provide references.

Human immunodeficiency virus (HIV) reverse transcriptase (RT) works in the life cycle of HIV and is one of the key targets for anti-HIV-1 drug development. Recently, a novel series of diarylpyrimidine derivatives (DAPYs) have been reported as potent HIV-1 non-nucleoside RT inhibitors (NNRTIs), and they exhibit potent antiviral activity. Here we explored the binding interaction patterns of a set of 2,4,5-trisubstituted pyrimidine derivatives using molecular docking, three-dimensional quantitative structure–activity relationships (3D-QSAR), and molecular dynamics (MD) simulations. Molecular docking for exploring the mechanism of action of small molecule ligands with receptor proteins. Comparative molecular field (CoMFA q2 = 0.828, r2 = 0.988, r2pred = 0.981) and comparative molecular similarity index (CoMSIA q2 = 0.859, r2 = 0.968, r2pred = 0.980) were performed to build stable and reliable 3D-QSAR models. The contour plots revealed the relationship between structural features and inhibitory activities. Based on the molecular docking analysis and contour maps, some novel compounds with higher predicted activities were designed and further MD simulations and bind free energy calculations were performed. Our models results may provide an essential reference for the design and development of effective novel HIV-1 NNRTIs. [ABSTRACT FROM AUTHOR]