Decreased Expression of the Host Long-Noncoding RNA-GM Facilitates Viral Escape by Inhibiting the Kinase activity TBK1 via S-glutathionylation.

Viruses have evolved multiple strategies to evade elimination by the immune system. Here we examined the contribution of host long noncoding RNAs (lncRNAs) in viral immune evasion. By functional screening of lncRNAs whose expression decreased upon viral infection of macrophages, we identified a lncRNA (lncRNA-GM, Gene Symbol: AK189470.1) that promoted type I interferon (IFN-I) production and inhibited viral replication. Deficiency of lncRNA-GM in mice increased susceptibility to viral infection and impaired IFN-I production. Mechanistically, lncRNA-GM bound to glutathione S-transferase M1 (GSTM1) and blocked GSTM1 interaction with the kinase TBK1, reducing GSTM1-mediated S-glutathionylation of TBK1. Decreased S-glutathionylation enhanced TBK1 activity and downstream production of antiviral mediators. Viral infection reprogrammed intracellular glutathione metabolism and furthermore, an oxidized glutathione mimetic could inhibit TBK1 activity and promote viral replication. Our findings reveal regulation of TBK1 by S-glutathionylation and provide insight into the viral mediated metabolic changes that impact innate immunity and viral evasion.

Binding Mechanism of Nitro Musks to Human Lactoferrin: Multispectral Approach, Docking and Molecular Dynamics Simulation.

Nitro musks are highly bioaccumulative and potentially carcinogenic, commonly used as additives in fabric softeners, detergents, and other household products. Furthermore, these substances have been detected in breast milk and human adipose tissue, posing a risk of direct exposure to pregnant women and infants. Human lactoferrin (HLF) is abundant in colostrum, and plays an important role in the non-specific immune system of the human body. In this study, the mechanisms of action of two nitro musk compounds, typical examples of synthetic musks, with HLF were investigated using molecular docking, dynamics simulation and multispectral methods. The fluorescence findings demonstrated that nitro musks quenched the intrinsic fluorescence of human lactoferrin through static quenching. Thermodynamic analysis of the binding parameters suggested that hydrophobic interactions acted synergistically in the formation of the complex. Moreover, analyses utilizing multispectral techniques, such as Fourier transform infrared (FTIR) spectroscopy, validated that the microenvironment and structure of HLF were altered in the presence of nitro musks. Finally, molecular docking and molecular dynamics simulations were employed to explore the specific binding mode of nitro musks with HLF and to assess the stability of the complex. These findings may provide a reference for assessing health risks to pregnant women and infants.

A Review of the Ethical Use of Animals in Functional Experimental Research in China Based on the "Four R" Principles of Reduction, Replacement, Refinement, and Responsibility.

Use of live laboratory animals is essential in the process of functional experimentation teaching. There are ethical problems, such as poor experimental environment, non-standard operation, and neglect of animal rights in experimental teaching. As an important basic course in life science education, functional experimentation should establish the correct ethics of use of laboratory animals. The welfare of laboratory animals has become one of the frontier directions of medical ethics research. The "4R" principle of animal welfare is based on the principles of reduction, replacement, refinement, and responsibility, which may provide a way to solve ethical problems in the teaching and research activities of functional experimentation. In addition to receiving relevant knowledge and education, laboratory animal practitioners and students in functional experimentation teaching should consciously abide by relevant regulations and rules and actively follow the "4R" principles. Animal ethics education is reflected in all teaching and research activities. Based on the principle of "4R" and the premise of guaranteeing teaching objectives, virtual simulation experiment teaching is a great supplement to functional experimentation. In teaching, medical ethics education should be strengthened to cultivate the consciousness of respecting the life of experimental animals, and awareness of laboratory animal ethics should be improved among teachers and students of functional experimentation to further promote ideological and political education in colleges and universities. This brief summary analyzes the general situation of animal ethics in functional experimentation in China based on the principle of "4R" and provides certain references and support for course teaching and training.

Integrated transcriptomic and metabolomic analysis of the hepatotoxicity of dichloroacetonitrile.

Dichloroacetonitrile (DCAN), an emerged nitrogenous disinfection by-product (N-DBP) in drinking water, has garnered attention owing to its strong cytotoxicity, genotoxicity, and carcinogenicity. However, there are limited studies on its potential hepatotoxicity mechanisms. Understanding hepatotoxicity is essential in order to identify and assess the potential risks posed by environmental pollutants on liver health and to safeguard public health. Here, we investigated the viability, reactive oxygen species (ROS) levels, and cell cycle profile of DCAN-exposed HepG2 cells and analyzed the mechanism of DCAN-induced hepatotoxicity using both transcriptomic and metabolomic techniques. The study revealed that there was a decrease in cell viability, increase in ROS production, and increase in the number of cells in the G2/M phase with an increase in the concentration of DCAN. Omics analyses showed that DCAN exposure increased cellular ROS levels, leading to oxidative damage in hepatocytes, which further induced DNA damage, cell cycle arrest, and cell growth impairment. Thus, DCAN has significant toxic effects on hepatocytes. Integrated analysis of transcriptomics and metabolomics offers new insights into the mechanisms of DCAN-induced hepatoxicity.

[Interpretation of new concepts and approaches in the ESICM guidelines on acute respiratory distress syndrome: definition, phenotyping and respiratory support strategies].

Acute respiratory distress syndrome (ARDS) continues to be one of the most life-threatening conditions for patients in the intensive care unit (ICU). The 2023 European Society of Intensive Care Medicine guidelines on ARDS: definition, phenotyping and respiratory support strategies (2023 Guideline) update the 2017 An Official American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine clinical practice guideline: mechanical ventilation in adult patients with ARDS (2017 Guideline), including 7 aspects of 3 topics of definitions, phenotyping, and respiratory support strategies [including high flow nasal cannula oxygen (HFNO), non-invasive ventilation (NIV), neuromuscular blocking agents (NMBA), extracorporeal life support (ECLS), positive end-expiratory pressure (PEEP) with recruitment maneuvers (RM), tidal volume (VT), and prone positioning]. 2023 Guideline review and summarize the literature since the publication of the 2017 Guideline, covering ARDS and acute hypoxemic respiratory failure, as well as ARDS caused by novel coronavirus infection. Based on the most recent medical evidence, the 2023 Guideline provide clinicians with new ideas and approaches for nonpharmacologic respiratory support strategies for adults with ARDS. This article provides interpretation of the new concepts, the new approaches, the new recommended grading and new levels of evidence for ARDS in the 2023 Guideline.

Establishment and Evaluation of Intelligent Diagnostic Model for Ophthalmic Ultrasound Images Based on Deep Learning.

OBJECTIVE: The goal of the work described here was to construct a deep learning-based intelligent diagnostic model for ophthalmic ultrasound images to provide auxiliary analysis for the intelligent clinical diagnosis of posterior ocular segment diseases. METHODS: The InceptionV3-Xception fusion model was established by using two pre-trained network models-InceptionV3 and Xception-in series to achieve multilevel feature extraction and fusion, and a classifier more suitable for the multiclassification recognition task of ophthalmic ultrasound images was designed to classify 3402 ophthalmic ultrasound images. The accuracy, macro-average precision, macro-average sensitivity, macro-average F1 value, subject working feature curves and area under the curve were used as model evaluation metrics, and the credibility of the model was assessed by testing the decision basis of the model using a gradient-weighted class activation mapping method. RESULTS: The accuracy, precision, sensitivity and area under the subject working feature curve of the InceptionV3-Xception fusion model on the test set reached 0.9673, 0.9521, 0.9528 and 0.9988, respectively. The model decision basis was consistent with the clinical diagnosis basis of the ophthalmologist, which proves that the model has good reliability. CONCLUSION: The deep learning-based ophthalmic ultrasound image intelligent diagnosis model can accurately screen and identify five posterior ocular segment diseases, which is beneficial to the intelligent development of ophthalmic clinical diagnosis.

Effects of healthcare failure mode and effect analysis on the prevention of multi-drug resistant organisms infections in oral and maxillofacial surgery.

OBJECTIVE: Care models of Healthcare Failure Mode and Effect Analysis (FMEA) were evaluated for the prevention of multi-drug resistant organisms (MDRO) infections in oral and maxillofacial surgery. METHODS: Two hundred patients who received oral and maxillofacial surgery from January to December 2017 were enrolled as the control group, and another 200 patients who received oral and maxillofacial surgery from January to December 2018 were enrolled as the FMEA group. The incidence of MDRO, the implementation of preventive and control measures, the mastery of preventive and control knowledge, and oral self-care ability were compared between the two groups. Risk Priority Number (RPN) and behavioral changes of health care personnel were observed in FMEA group. RESULTS: The FMEA group had a lower incidence of MDRO (2.00%) than the control group (6.00%) and a higher rate of acquisition of prevention and control knowledge (93.00%) than the control group (84.50%) (P < 0.05). Patients in FMEA group were higher than those in the control group in terms of compliance towards isolation signs and precautions, appropriate use of PPE, implementation of disinfection measures, hand hygiene and exercise of self-care agency (ESCA) scale scores (P < 0.05). The total RPN score of the FMEA group before and after management was 1384 and 180, respectively, and the reduction rate of total RPN scores was 86.99%. Scores with regard to knowledge, attitude, and behavior of health care personnel were increased after FMEA treatment (P < 0.05). CONCLUSION: The nursing model of FMEA for oral and maxillofacial surgery can prevent MDRO infections, reduce RPN, improve the implementation of preventive and control measures as well as oral self-care ability and the acquisition of knowledge.

IRF3-binding lncRNA-ISIR strengthens interferon production in viral infection and autoinflammation.

Interferon regulatory factor 3 (IRF3) is an essential transductor for initiation of many immune responses. Here, we show that lncRNA-ISIR directly binds IRF3 to promote its phosphorylation, dimerization, and nuclear translocation, along with enhanced target gene productions. In vivo lncRNA-ISIR deficiency results in reduced IFN production, uncontrolled viral replication, and increased mortality. The human homolog, AK131315, also binds IRF3 and promotes its activation. More important, AK131315 expression is positively correlated with type I interferon (IFN-I) level and severity in patients with lupus. Mechanistically, in resting cells, IRF3 is bound to suppressor protein Flightless-1 (Fli-1), which keeps its inactive state. Upon infection, IFN-I-induced lncRNA-ISIR binds IRF3 at DNA-binding domain in cytoplasm and removes Fli-1's association from IRF3, consequently facilitating IRF3 activation. Our results demonstrate that IFN-I-inducible lncRNA-ISIR feedback strengthens IRF3 activation by removing suppressive Fli-1 in immune responses, revealing a method of lncRNA-mediated modulation of transcription factor (TF) activation.

Development and validation of a discrimination model between primary PLA2R-negative membranous nephropathy and minimal change disease confirmed by renal biopsy.

Membranous nephropathy (MN) and minimal change disease (MCD) are two common causes leading to nephrotic syndrome (NS). They have similar clinical features but different treatment strategies and prognoses. M-type phospholipase A2 receptor (PLA2R) is considered as a specific marker of membranous nephropathy. However, its sensitivity is only about 70%. Therefore, there is a lack of effective and noninvasive tools to distinguish PLA2R-negative MN and MCD patients without renal biopsy. A total 949 patients who were pathologically diagnosed as idiopathic MN or MCD were enrolled in this study, including 805 idiopathic MN and 144 MCD. Based on the basic information and laboratory examination of 200 PLA2R-negative MN and 144 MCD, we used a univariate and multivariate logistic regression to select the relevant variables and develop a discrimination model. A novel model including age, albumin, urea, high density lipoprotein, C3 levels and red blood cell count was established for PLA2R-negative MN and MCD. The discrimination model has great differential capability (with an AUC of 0.904 in training group and an AUC of 0.886 in test group) and calibration capability. When testing in all 949 patients, our model also showed good discrimination ability for all idiopathic MN and MCD.

Effect of inorganic/organic ratio and chemical coupling on the performance of porous silica/chitosan hybrid scaffolds.

Inorganic/organic hybrid scaffolds have great potential for tissue engineering applications due to controllable mechanical properties and tailorable biodegradation. Here, silica/chitosan hybrid scaffolds were fabricated through the sol-gel method with a freeze drying process. 3-Glycidoxypropyl trimethoxysilane (GPTMS) and tetraethylorthosilicate (TEOS) were used as the covalent inorganic/organic coupling agent and the separate inorganic source, respectively. Hybrid scaffolds with various inorganic/organic weight ratios (I/Os) and molar ratios of chitosan and GPTMS (GCs) were examined and compared in this study. FTIR showed that higher GPTMS content resulted in the increased covalent cross-linking of the chitosan and the silica network in hybrids. Compression testing indicated that increasing the GPTMS content greatly improved the compressive strength of scaffold. LIVE/DEAD assay showed that enhanced cytocompatibility was obtained as the silica content increased. Therefore, the results confirmed that the two parameters I/O and GC can largely influence the scaffold performance, which can be used to tailor the hybrid properties.