Ubiquitylation of RUNX3 by RNA-binding ubiquitin ligase MEX3C promotes tumorigenesis in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most common pathological type of lung cancer, but the early diagnosis rate is low. The RNA-binding ubiquitin ligase MEX3C promotes tumorigenesis in several cancers but its mechanism of action in LUAD is unclear. In this study, the biological activity of MEX3C was assessed in LUAD. MEX3C and RUNX3 mRNA levels in the tissues of LUAD patients were determined using reverse transcription­quantitative PCR. The involvement of MEX3C in the growth and metastasis of LUAD cells was measured by EdU assay, CCK-8, colony formation, Transwell assay, TUNEL, and flow cytometry. Expression of apoptosis and epithelial-mesenchymal transition related proteins were determined using western blotting analysis. LUAD cells transfected with si-MEX3C were administered to mice subcutaneously to monitor tumor progression and metastasis. We found that MEX3C is strongly upregulated in LUAD tissue sections, and involved in proliferation and migration. A549 and H1299 cells had significantly higher levels of MEX3C expression compared to control HBE cells. Knockdown of MEX3C dramatically decreased cell proliferation, migration, and invasion, and accelerated apoptosis. Mechanistically, we demonstrate MEX3C induces ubiquitylation and degradation of tumor suppressor RUNX3. Moreover, RUNX3 transcriptionally represses Suv39H1, as revealed by RNA pull-down and chromatin immunoprecipitation assays. The in vivo mice model demonstrated that knockdown of MEX3C reduced LUAD growth and metastasis significantly. Collectively, we reveal a novel MEX3C-RUNX3-Suv39H1 signaling axis driving LUAD pathogenesis. Targeting MEX3C may represent a promising therapeutic strategy against LUAD.

Long Non-Coding RNA BCYRN1 Drives Cellular Processes to Promote Asthma Development.

INTRODUCTION: Asthma is a common chronic inflammatory respiratory disease worldwide. The long non-coding RNA (lncRNA) BCYRN1 has been shown to function in the inhibition of smooth muscle cell differentiation and vascular development, but its function and potential molecular mechanisms of lncRNA BCYRN1 in bronchial smooth muscle cells (BSMCs) in asthma remain unknown. METHODS: Quantitative real-time polymerase chain reaction (RT-qPCR) was performed to detect the expression level of lncRNA BCYRN1 in blood and sputum of asthma patients. The effects of lncRNA BCYRN1 on the proliferation and migration of BSMCs were explored by cell counting kit-8, Transwell, colony formation, and flow cytometry analysis. Differentially expressed genes between lncRNA BCYRN1 overexpression and knockdown cells were identified using RNA-seq and verified using RT-qPCR. RESULTS: LncRNA BCYRN1 was upregulated in asthma patients. Overexpression of lncRNA BCYRN1 significantly promoted the proliferation and migration of BSMCs, inhibited cell apoptosis and affected cell cycle arrest, promoting DNA replication. These effects were reversed after lncRNA BCYRN1 inhibition. RNA-seq identified 434 common differentially expressed genes in the lncRNA BCYRN1 overexpression and knockdown groups and verified their expression levels by RT-qPCR. Gene ontology, Kyoto Encyclopedia of Genes and Genomes and Gene set enrichment analysis indicated that these genes were mainly involved in external stimulus, cell cycle, growth factor activity, cytokine interactions, and inflammatory response. CONCLUSION: The identification of the highly expressed lncRNA BCYRN1 in patients with asthma, combined with functional experiments and transcriptional data, suggests that lncRNA BCYRN1 can mediate the development of asthma and can be used as a promising diagnostic and prognostic biomarker for asthma.

Placenta-derived mesenchymal stem cells promote diabetic wound healing via exosomal protein interaction networks.

There is a lack of effective treatment options for diabetic refractory wounds, which presents a critical clinical issue that needs to be addressed urgently. Our research has demonstrated that human placenta-derived mesenchymal stem cells (plaMSCs) facilitate the migration and proliferation of HaCat cells, thereby enhancing diabetic wound healing primarily via the exosomes derived from plaMSCs (plaMSCs-Ex). Using label-free proteomics, plaMSCs and their exosomes were analysed for proteome taxonomic content in order to explore the underlying effective components mechanism of plaMSCs-Ex in diabetic wound healing. Differentially expressed proteins enriched in plaMSCs-Ex were identified and underwent bioinformatics analysis including GO annotation, KEGG pathway enrichment, gene set enrichment analysis (GSEA) and protein-protein interaction analysis (PPI). Results showed that the proteins enriched in plaMSCs-Ex are significantly involved in extracellular matrix organisation, epithelium morphogenesis, cell growth, adhesion, proliferation and angiogenesis. PPI analysis filtered 2 wound healing-related clusters characterised by hub proteins such as POSTN, FN1, SPARC, TIMP1, SERPINE1, LRP1 and multiple collagens. In brief, the exosomal proteins derived from plaMSCs reveal diverse functions of regeneration and tissue remodelling based on proteomics analysis and potentially play a role in diabetic wound healing.

Long-Term Outcomes of Diastasis Recti Abdominis in Postpartum Women: A Retrospective Cohort Study.

INTRODUCTION AND HYPOTHESIS: The objective was to investigate whether diastasis recti abdominis (DRA) can cause adverse outcomes for different long-term postpartum women. METHODS: We recruited 437 long-term postpartum women at five different time points (3, 5, 10, 20, and 30 years postpartum respectively). Inter-recti distance (IRD) and linea alba or umbilical hernia were measured by ultrasound. Strength of abdominal muscle was measured by a manual muscle test. Low back pain (LBP), urinary incontinence (UI) and quality of life (QOL) were measured by questionnaires including the Oswestry Disability Index, the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form, 36-Item Short Form Health Survey respectively. RESULTS: Women with DRA experienced more severe LBP, and poorer QOL only 10 years postpartum according to the diagnostic criterion of IRD > 2cm. However, when the diagnostic criterion was raised to IRD > 3cm, women with DRA reported weaker abdominal muscle strength, more severe LBP 3, 5, and 10 years postpartum, poorer QOL 3, 5, 10, and 20 years postpartum, and higher incidence of linea alba or umbilical hernia 5 and 20 years postpartum. CONCLUSIONS: When using IRD > 2cm as the diagnostic criterion, the impact of DRA is minimal. However, when utilizing IRD > 3cm as the diagnostic criterion, DRA is associated with increased linea alba or umbilical hernia, weakened abdominal muscle strength, increased LBP, and decreased QOL. Most of the effects are particularly evident within 3-10 years postpartum, but becomes insignificant 20 and 30 years postpartum. Therefore, it is necessary to consider whether the diagnostic criterion of DRA need to be improved.

Epidemiology and Clinical Characteristics of Pediatric Sepsis in PICUs in Southwest China: A Prospective Multicenter Study.

OBJECTIVES: To describe the epidemiological characteristics of pediatric sepsis in Southwest China PICUs. DESIGN: A prospective, multicenter, and observational study. SETTING: Twelve PICUs in Southwest China. PATIENTS: The patients admitted to the PICU from April 1, 2022, to March 31, 2023. The age ranged from 28 days to 18 years. All patients met the criteria of severe sepsis or septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 31 PICUs invited to participate, 12 PICUs (capacity of 292 beds) enrolled patients in the study. During the study period, 11,238 children were admitted to the participating PICUs, 367 (3.3%) of whom met the diagnosis of severe sepsis or septic shock. The most prevalent sites of infection were the respiratory system (55%) and the digestive system (15%). The primary treatments administered to these patients included antibiotics (100%), albumin (61.3%), invasive mechanical ventilation (58.7%), glucocorticoids (55.6%), blood products (51%), gammaglobulin (51%), and vasoactive medications (46.6%). Sepsis-related mortality in the PICU was 11.2% (41/367). Nearly half of the sepsis deaths occurred within the first 3 days of PICU admission (22/41, 53.7%). The mortality rate of septic shock (32/167, 19.2%) was significantly higher than that of severe sepsis (9/200, 4.5%; p < 0.001). The outcomes of a multivariate logistic regression analysis suggested that a higher pediatric Sequential Organ Failure Assessment score, and the use of invasive mechanical ventilation and vasoactive medications were independently associated with PICU mortality in children with sepsis. CONCLUSIONS: This report updates the epidemiological data of pediatric sepsis in PICUs in Southwest China. Sepsis is still a life-threatening disease in children.

Association of Delirium with Long-Term Mortality in Critically Ill Patients with COPD Who Survived to Discharge: A Retrospective Cohort Study.

BACKGROUND: Critically ill patients with chronic obstructive pulmonary disease (COPD) face significant mortality after hospital discharge. Delirium is common in patients with COPD, but its impact on long-term mortality in critically ill COPD patients who survive to discharge remains uncertain. METHODS: Critically ill patients with COPD who survived to discharge were selected from the Medical Information Mart for Intensive Care IV database. Delirium was assessed using the Confusion Assessment Method for Intensive Care Unit. The primary outcome was 365- and 180-day mortality after discharge. The secondary outcomes included 90- and 30-day mortality following discharge, length of intensive care unit (ICU) and hospital stays, and nursing care needs after hospital discharge. RESULTS: Of the 2621 survivors of critically ill COPD patients, 982 had suffered delirium during their ICU stay and 709 died within 365 days after hospital discharge. Delirium was significantly associated with 365-day mortality after hospital discharge (adjusted hazard ratio [HR] 1.22; 95% confidence interval [CI] 1.02-1.47). The results were consistent for 180-, 90-, and 30-day post-discharge mortality (adjusted HR [95% CI]: 1.35 [1.09-1.66], 1.48 [1.16-1.89], and 1.68 [1.21-2.32], respectively). Additionally, patients with delirium had longer ICU and hospital stay (adjusted ß 2.75; 95% CI 2.35-3.16 and 4.25; 95% CI 3.51-4.98, respectively) and increased nursing care needs after hospital discharge (adjusted odds ratio, 1.56; 95% CI 1.13-2.14). CONCLUSION: ICU delirium was an independent risk factor for both long-term and short-term mortality in critically ill patients with COPD who survived to discharge.

Social anxiety and loneliness among older adults: a moderated mediation model.

BACKGROUND: Few studies have clarified the mechanisms linking social anxiety and loneliness in older populations. The study aimed to explore how social network mediate the relationship between social anxiety and loneliness in older adults, with perceived social support playing a moderating role. METHODS: A total of 454 older patients completed the Social Avoidance and Distress Scale, Lubben Social Network Scale-6, Chinese version of the Short Loneliness Scale and Perceived Social Support Scale. Bootstrap and simple slope methods were used to test the moderated mediation model. RESULTS: Social anxiety had a significant positive predictive effect on loneliness and social network partially mediated this relationship. The relationship between social anxiety and social network, as well as the relationship between social network and loneliness, was moderated by perceived social support. Specifically, perceived social support buffered the effects of social anxiety on social network, but the buffering effect diminished with increasing levels of social anxiety. On the social network and loneliness pathway, the social network of older persons with higher perceived social support has a stronger prediction of loneliness. CONCLUSIONS: The study found that social anxiety can contribute to loneliness by narrowing older adults' social network. High perceived social support can buffer this process, but do not overstate its protective effects. Thus, interventions to reduce social anxiety and improve social network and social support may help prevent and alleviate loneliness in older adults.

Comparison of diffusion ranges at different local anesthetic volumes during superior laryngeal nerve block.

OBJECTIVES: Ultrasound-guided superior laryngeal nerve (SLN) block is a practical and painless approach to avoid the hemodynamic stress response during endotracheal intubation and relieve sore throat after laryngeal surgery. The main purpose of this study was to establish an optimal dosage of local anesthetic when performing SLN block to help anesthetists balance analgesia and side effects. METHODS: Twenty fresh larynx specimens were obtained immediately after resection and then injected with 2-, 3-, 4-, or 5- mL of a lidocaine-blue dye mixture at bilateral SLN puncture sites. Superficial areas of deposited blue dye were measured. Dye leakage and surrounding dyed tissue were recorded. Another 40 patients were included in the ultrasound investigation. Distances between the internal branch of the SLN (iSLN) and adjacent structures were calculated. RESULTS: The dye spread area was greater with the administration of larger doses, especially to the visceral space. A 2- or 3-mL injection of local anesthetic was sufficient to infiltrate the SLN gap. A higher incidence of dye leaking out of the thyrohyoid membrane and anterior epiglottis space was observed; furthermore, there was substantially more dyed hyoid/thyroid cartilage with 4 and 5 mL of injected dye mixture than 2 mL. There was no significant difference between the specimen and ultrasound measurements of for length of iSLN-adjacent structures. CONCLUSIONS: In the Chinese population, 2- or 3- mL of local anesthetic is a safe dose during SLN block. A larger volume could overflow from the cavity to cause complications. The thyrohyoid membrane combined with the superior laryngeal artery is a reliable target for positioning the iSLN during ultrasound-guided regional anesthesia.

Assessment of the Significance and Clinical Implications of Stress Hormones in Acute Pressure Injuries Among Trauma Patients.

Objective: This study examines the dynamic changes of stress hormones, including insulin (INS), fasting blood glucose (FBG), glucagon (Glu), and cortisol (Cort), in trauma patients. By monitoring these changes and observing acute pressure injury (API) occurrences on the skin, the research analyzes the influence of stress hormones on API development in trauma patients. Methods: A prospective analysis involved 218 trauma patients admitted to a grade III-A general hospital in Wenzhou from April 2021 to June 2023. Among them, 44 cases developed API (API group), and 174 cases did not (control group). Levels of INS, Cort, Glu, and FBG were measured in both groups. Additionally, Abbreviated Injury Scale-Injury Severity Score (AIS-ISS) surveys and API severity assessments were conducted. Correlations between stress hormone levels and AIS-ISS were discussed. The predictive effects of AIS-ISS and stress hormones on API occurrence in trauma patients were analyzed using receiver operating characteristic (ROC) curves. The relationship between stress hormone levels and API severity was also observed. Results: Study's outcomes indicated distinct relationships between stress hormone levels and API occurrence in trauma patients. Specifically, INS demonstrated a negative correlation with AIS-ISS, highlighting its potential as a significant factor. Glu, Cort, and FBG revealed positive associations, emphasizing their roles in influencing API development (P < .05). The diagnostic efficacy of stress hormones in predicting API occurrence, as represented by the Area Under Curve (AUC) = 0.8100. Notably, within the API group, INS levels demonstrated a decline with worsening API. Conversely, Glu, Cort, and FBG exhibited increases in tandem with the aggravation of API symptoms (P < .05). Conclusions: This research suggests that assessing stress hormone levels in clinical settings can effectively predict API occurrence. Early testing could aid in the development of preventive or intervention measures, reducing the incidence and harm of API in trauma patients.

UHPLC-PDA-Q-TOF-MS-α-amylase-FLD activity detection system and molecular docking.

INTRODUCTION: Traditional and some scientific literature document the antidiabetic effects of the Ziziphi Spinosae Semen (ZSS). However, the bioactive compounds of ZSS responsible for the antidiabetic effects are not well known. OBJECTIVES: This study aimed to investigate the material basis of the antidiabetic effects of ZSS by inhibiting α-amylase. METHODOLOGY: An online analysis platform was established and optimized using an ultra-performance liquid chromatography-photo-diode array-quadrupole-time-of-flight-mass spectrometry-α-amylase-fluorescence detector (UHPLC-PDA-Q-TOF-MS-α-amylase-FLD) system to screen α-amylase inhibitors in ZSS rapidly. The inhibitory effect of these compounds was confirmed by molecular docking screening. and the molecular interactions between α-amylase and active compounds were evaluated, which strongly supported the experimental results. RESULTS: Seventy-eight compounds were identified in the ZSS extract, eleven of which were screened to have significant α-amylase binding activity. CONCLUSION: This study demonstrated the feasibility of using an established platform to screen for effective components in ZSS, providing a practical method for the rapid screening of potential antidiabetic active ingredients in traditional Chinese medicine.

Protectin Conjugates in Tissue Regeneration 1 Inhibits Macrophage Pyroptosis by Restricting NLRP3 Inflammasome Assembly to Mitigate Sepsis via the cAMP-PKA Pathway.

Protectin conjugates in tissue regeneration 1 (PCTR1) is a novel anti-inflammatory and proresolving lipid mediator biosynthesized from docosahexaenoic acid. Excessive activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome and consequent pyroptosis are involved in diverse inflammatory diseases. However, how PCTR1 affects NLRP3 inflammasome activation and pyroptosis are still unclear. Here, we demonstrated that PCTR1 inhibited NLRP3 inflammasome activation and pyroptosis. These results show that PCTR1 dose-dependently inhibited gasdermin D cleavage in lipopolysaccharide (LPS)-primed murine primary macrophages upon nigericin stimulation. Additionally, PCTR1 treatment after LPS priming inhibited caspase-1 activation and subsequent mature interleukin-1ß release independent of the nuclear factor-kappa B pathway. PCTR1 exerted its inhibitory effects by blocking NLRP3-apoptosis-associated speck-like protein containing a CARD (ASC) interaction and ASC oligomerization, thereby restricting NLRP3 inflammasome assembly. However, the inhibitory effect of PCTR1 could be reversed by KH7 and H89, which are the inhibitors of the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling pathway. Moreover, PCTR1 treatment alleviated lung tissue damage and improved mouse survival in LPS-induced sepsis. Our study unveils the molecular mechanism of negative regulation of NLRP3 inflammasome activation and pyroptosis by a novel lipid mediator and suggests that PCTR1 may serve as a potential treatment option for NLRP3-inflammasome driven diseases.

KIF23, under regulation by androgen receptor, contributes to nasopharyngeal carcinoma deterioration by activating the Wnt/ß-catenin signaling pathway.

Our study aimed to explore the potential mechanisms of KIF23 regulating function in the progression of nasopharyngeal carcinoma and pinpoint novel therapeutic targets for the clinical treatment of nasopharyngeal carcinoma patients. Firstly, the mRNA and protein level of KIF23 in nasopharyngeal carcinoma was measured using quantitative real-time PCR and western blot. Then, the influence of KIF23 on tumor metastasis and growth in nasopharyngeal carcinoma was determined through the in vivo and in vitro experiments. Lastly, the regulatory mechanisms of KIF23 in nasopharyngeal carcinoma were illustrated in the chromatin immunoprecipitation assay. KIF23 was first found to be overexpressed in nasopharyngeal carcinoma samples, and its expression was associated with poor prognosis. Then, the nasopharyngeal carcinoma cell's proliferation, migration, and invasion potential could be improved by inducing KIF23 expression both in vivo and in vitro. Furthermore, androgen receptor (AR) was found to bind to the KIF23 promoter region directly and enhance KIF23 transcription. At last, KIF23 could accelerate nasopharyngeal carcinoma deterioration via activating the Wnt/ß-catenin signaling pathway. AR/KIF23/Wnt/ß-catenin pathway promotes nasopharyngeal carcinoma deterioration. Our findings could serve as a new therapeutic strategy for nasopharyngeal carcinoma in the clinical practice.

The antimicrobial activity of cethromycin against Staphylococcus aureus and compared with erythromycin and telithromycin.

BACKGROUND: This study aims to explore the antibacterial activity of cethromycin against Staphylococcus aureus (S. aureus), and its relationship with multilocus sequence typing (MLST), erythromycin ribosomal methylase (erm) genes and macrolide-lincosamide-streptogramin B (MLSB) phenotypes of S. aureus. RESULTS: The minimum inhibitory concentrations (MICs) of cethromycin against 245 S. aureus clinical isolates ranged from 0.03125 to ≥ 8 mg/L, with the resistance of 38.8% in 121 methicillin-resistant S. aureus (MRSA). This study also found that cethromycin had strong antibacterial activity against S. aureus, with the MIC ≤ 0.5 mg/L in 55.4% of MRSA and 60.5% of methicillin-sensitive S. aureus (MSSA), respectively. The main MLSTs of 121 MRSA were ST239 and ST59, and the resistance of ST239 isolates to cethromycin was higher than that in ST59 isolates (P = 0.034). The top five MLSTs of 124 MSSA were ST7, ST59, ST398, ST88 and ST120, but there was no difference in the resistance of MSSA to cethromycin between these STs. The resistance of ermA isolates to cethromycin was higher than that of ermB or ermC isolates in MRSA (P = 0.016 and 0.041, respectively), but the resistance of ermB or ermC isolates to cethromycin was higher than that of ermA isolates in MSSA (P = 0.019 and 0.026, respectively). The resistance of constitutive MLSB (cMLSB) phenotype isolates to cethromycin was higher than that of inducible MLSB (iMLSB) phenotype isolates in MRSA (P < 0.001) or MSSA (P = 0.036). The ermA, ermB and ermC genes was mainly found in ST239, ST59 and ST1 isolates in MRSA, respectively. Among the MSSA, the ermC gene was more detected in ST7, ST88 and ST120 isolates, but more ermB genes were detected in ST59 and ST398 isolates. The cMLSB phenotype was more common in ST239 and ST59 isolates of MRSA, and was more frequently detected in ST59, ST398, and ST120 isolates of MSSA. CONCLUSION: Cethromycin had strong antibacterial activity against S. aureus. The resistance of MRSA to cethromycin may had some clonal aggregation in ST239. The resistance of S. aureus carrying various erm genes or MLSB phenotypes to cethromycin was different.

Neural stem cell transplantation improves neurological function in focal cerebral ischemia through GDNF/PI3K/AKT axis.

The aim of this experiment was to analyze the ameliorating effect of neural stem cells (NSCs) on focal cerebral ischemia (FCI) through GDNF/PI3K/AKT axis, so as to provide evidence for future clinical application of NSCs. In this study, the 15 Sprague-Dawley (SD) male rats were modeled for middle cerebral artery occlusion (MCAO)-induced FCI and then grouped: NSCs group was treated with NSC transplantation, GDNF/NSCs group was transplanted with recombinant adenovirus pAdEasy-1-pAdTrackCMV-GDNF-transfedcted NSCs, and the blank group was treated with normal saline transplantation. Rats were tested by rotarod and corner turn tests at 1 week and 4 weeks after NSC transplantation, and the levels of tumor necrosis factor-α (TNF-α), interleukin-6/8 (IL-6/8), superoxide dismutase (SOD) and malondialdehyde (MDA) were quantified. Then all rats were killed and their brain tissues were HE stained for the determination of and GDNF/PI3K/AKT axis-associated protein expression. The results of the experiment showed that: at the 1st and 4th week after transplantation, the time on the rod, number of turnings and SOD were the lowest in the blank group among the three groups, while IL-6, IL-8, TNF-α and MDA were the highest (P<0.05). Increased time on the rod, number of turnings and SOD, as well as decreased IL-6, IL-8, TNF-α and MDA were observed in NSCs and GDNF/NSCs groups after transplantation, with better performance in GDNF/NSCs group (P<0.05). Based on HE staining of brain tissue, GDNF/NSCs group had the most significant improvement in tissue injury and the highest GDNF, PI3K, AKT and p-AKT protein expression among the three groups (P<0.05). In conclusions, NSC transplantation can ameliorate neurological function in MCAO-induced FCI rats through the GDNF/PI3K/AKT axis.

Acyl-quinic acids from the root bark of Acanthopanax gracilistylus and their inhibitory effects on neutrophil elastase and cyclooxygenase-2 in vitro.

Eleven new acyl-quinic acids (AQAs) 1a-9, and 18 known AQAs 10-27 were isolated from the root bark of Acanthopanax gracilistylus W. W. Smith (Acanthopanacis Cortex). The planar structures of 1a-9 were determined based on their HR-ESIMS, IR, and NMR data. The absolute configurations of 1a-6 were identified by comparing the experimental and the calculated electronic circular dichroism (ECD) spectra. This is the first report of the isolation of AQAs from Acanthopanacis Cortex. Notably, 1a-6 were determined as unusual oxyneolignan-(-)-quinic acids heterodimers, representing a new class of natural products. The inhibitory activities of 1a-27 on neutrophil elastase (NE) and cyclooxygenase-2 (COX-2) were studied in vitro, and the results indicated they possessed significant inhibitory activities on COX-2. Among them, the IC50 values of 1a-9 were 0.63±0.014, 0.75±0.028, 0.15±0.023, 0.63±0.016, 0.30±0.013, 35.63±4.600, 8.70±1.241, 16.51±0.480, 0.69±0.049, 0.39±0.017, and 0.26±0.080 µM, respectively. This study represents the inaugural disclosure of the anti-COX-2 constituents found in Acanthopanacis Cortex, thereby furnishing valuable insights into the exploration of novel COX-2 inhibitors derived from natural reservoirs.

Association Between Endothelial Activation and Stress Index and 28-Day Mortality in Septic ICU patients: a Retrospective Cohort Study.

Background: Endothelial Activation and Stress Index (EASIX) is a reliable alternative biomarker of endothelial dysfunction. Because endothelial activation is involved in sepsis pathophysiology, we aimed to investigate the association between EASIX and prognosis in septic patients. Methods: Data were extracted from the Medical Information Mart for Intensive Care (MIMIC) IV database. EASIX scores were calculated using the formula: lactate dehydrogenase (U/L) × creatinine (mg/dL)/platelet count (109/L). Patients were grouped into tertiles according to log2 transformed EASIX. The primary and secondary outcomes were 28-day and 90-day mortality. Cox proportional hazards models, Kaplan-Meier curves, restricted cubic spline curves, and subgroup analyses were conducted to evaluate the association between EASIX and prognosis in septic patients. Results: A total of 7504 patients were included. Multivariable Cox proportional hazards analyses showed that higher log2-EASIX was associated with increased risk of 28-day mortality (HR, 1.10; 95% CI, 1.07-1.13; P < 0.001). Compared with tertile 1, the tertile 2 and 3 groups had higher risk of 28-day mortality [HR (95% CI) 1.24 (1.09-1.41); HR (95% CI) 1.51 (1.31-1.74)]; P for trend < 0.001). Similar results were found for 90-day mortality. Kaplan-Meier curves showed that patients with higher EASIX had lower 28-day and 90-day survival rates. A linear relationship was found between log2-EASIX and 28-day and 90-day mortality. Conclusion: High EASIX was significantly associated with an increased risk of 28-day and 90-day all-cause mortality in patients with sepsis.

Neobavaisoflavone Inhibits Biofilm Formation and α-Toxin Activity of Staphylococcus aureus.

Neobavaisoflavone had antimicrobial activities against Gram-positive multidrug-resistant (MDR) bacteria, but the effect of neobavaisoflavone on the virulence and biofilm formation of S. aureus has not been explored. The present study aimed to investigate the possible inhibitory effect of neobavaisoflavone on the biofilm formation and α-toxin activity of S. aureus. Neobavaisoflavone presented strong inhibitory effect on the biofilm formation and α-toxin activity of both methicillin-sensitive S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) strains at 25 µM, but did not affect the growth of S. aureus planktonic cells. Genetic mutations were identified in four coding genes, including cell wall metabolism sensor histidine kinase walK, RNA polymerase sigma factor rpoD, tetR family transcriptional regulator, and a hypothetical protein. The mutation of WalK (K570E) protein was identified and verified in all the neobavaisoflavone-induced mutant S. aureus isolates. The ASN501, LYS504, ILE544 and GLY565 of WalK protein act as hydrogen acceptors to form four hydrogen bonds with neobavaisoflavone by molecular docking analysis, and TRY505 of WalK protein contact with neobavaisoflavone to form a pi-H bond. In conclusion, neobavaisoflavone had excellent inhibitory effect on the biofilm formation and α-toxin activity of S. aureus. The WalK protein might be a potential target of neobavaisoflavone against S. aureus.

CD40LG-associated X-linked Hyper-IgM Syndrome (XHIGM) with pulmonary alveolar proteinosis: a case report.

BACKGROUND: D40LG-associated X-linked hyper-IgM syndrome with pulmonary alveolar proteinosis has rarely been reported, and its genotype-phenotypic correlation remains elusive. CASE PRESENTATION: We describe a five-month-old boy with CD40LG mutation (c.516T > A, p.Tyr172Ter) X-linked hyper-IgM syndrome with pulmonary alveolar proteinosis as the first manifestation. The patient completely recovered after immunotherapy and allogeneic hematopoietic stem cell transplantation. In addition, four previously reported patients with CD40LG mutation with pulmonary alveolar proteinosis were also analyzed. All of these patients presented with early onset of pulmonary infections and a good response to immunotherapy. The structural model of CD40LG indicated that all mutations caused the X-linked hyper-IgM syndrome with pulmonary alveolar proteinosis to be located within the tumor necrosis factor homology domain. CONCLUSIONS: A case was presented, and the characteristics of four cases of CD40LG-associated X-linked hyper-IgM syndrome with pulmonary alveolar proteinosis were summarized. The variant locations may explain the phenotypic heterogeneity of patients with the CD40LG mutation.

HIV protease inhibitor saquinavir inhibits toll-like receptor 4 activation by targeting receptor dimerization.

OBJECTIVE: Toll-like receptor 4 (TLR4) is crucial in induction of innate immune response through recognition of invading pathogens or endogenous alarming molecules. Ligand-triggered dimerization of TLR4 is essential for the activation of NF-κB and IRF3 through MyD88- or TRIF-dependent pathways. Saquinavir (SQV), an FDA-approved HIV protease inhibitor, has been shown to attenuate the activation of NF-κB induced by HMGB1 by blocking TLR4-MyD88 association in proteasome independent pathway. This study aims to define whether SQV is an HMGB1-specific and MyD88-dependent TLR4 signaling inhibitor and which precise signaling element of TLR4 is targeted by SQV. MATERIALS AND METHODS: PMA differentiated human THP-1 macrophages or reconstituted HEK293 cells were pretreated with SQV before stimulated by different TLR agonists. TNF-α level was evaluated through ELISA assay. NF-κB activation was analyzed using NF-κB SEAP reporting system. The levels of MyD88/TRIF pathways-related factors were examined by immunoblot. TLR4 endocytosis was assessed by immunocytochemistry. TLR4 dimerization was determined using immunoprecipitation between different tagged TLR4 and an in silico molecular docking experiment was performed to explore the possible binding site of SQV on its target. RESULTS: Our data showed that SQV suppresses both MyD88- and TRIF-dependent pathways in response to lipopolysaccharide (LPS), a critical sepsis inducer and TLR4 agonist, leading to downregulation of NF-κB and IRF3. SQV did not suppress MyD88-dependent pathway triggered by TLR1/2 agonist Pam3csk4. In the only TRIF-dependent pathway, SQV did not alleviate IRF3 phosphorylation induced by TLR3 agonist Poly(I:C). Furthermore, dimerization of TLR4 following LPS or HMGB1 stimulation was decreased by SQV. CONCLUSION: We concluded that TLR4 receptor complex is one of the mammalian targets of SQV, and TLR4-mediated immune responses and consequent risk for uncontrolled inflammation could be modulated by FDA-approved drug SQV.

Carbon deficit checks in high resolution and compensation under regional inequity.

Carbon compensation is an effective way of reducing carbon emissions. However, previous studies in this field have been limited and have not examined high-precision scientific carbon compensation under regional inequity. The present study examined initial carbon compensation in the grid and developed a new equitable carbon compensation model. Additionally, it modified the carbon compensation value for each province and analysed how land-use change affected carbon compensation. The results show that, after the modification, the entire carbon deficit reached 17.34 × 108 t C in 2015, representing a decrease of 14% compared with the initial carbon deficit. The area with negative carbon deficit values accounted for 36% of the whole area, concentrated mainly in the south, southwest and northwest. Without modification, the initial carbon compensation reached 537 × 108 USD, and only Yunnan, Sichuan and Hainan provinces being eligible to receive compensation. The final modified carbon compensation was approximately 20% of the initial values, and 11 provinces were eligible to obtain compensation. The other provinces responsible for paying the carbon compensation costs were typically concentrated in Central and Eastern China. Land-use changes in 2015 led to increases in the initial carbon compensation and modified carbon compensation of 3.74 × 108 and 0.13 × 108 USD, respectively. The per-unit land-use change caused greater increases in carbon emissions in China's big cities and the provinces in Central and East China. Some policies, such as macro-control by the central government, diversified forms and patterns of compensation, and auxiliary measures should be formulated/proposed.