The exploration of perioperative hypotension subtypes: a prospective, single cohort, observational pilot study.

Background: Hypotension is a risk factor for postoperative complications, but evidence from randomized trials does not support that a higher blood pressure target always leads to optimized outcomes. The heterogeneity of underlying hemodynamics during hypotension may contribute to these contradictory results. Exploring the subtypes of hypotension can enable optimal management of intraoperative hypotension. Methods: This is a prospective, observational pilot study. Patients who were ≥ 45 years old and scheduled to undergo moderate-to-high-risk noncardiac surgery were enrolled in this study. The primary objective of this pilot study was to investigate the frequency and distribution of perioperative hypotension and its subtypes (hypotension with or without cardiac output reduction). The exposure of hypotension and its subtypes in patients with and without myocardial or acute kidney injury were also explored. Results: Sixty patients were included in the analysis. 83% (50/60) of the patients experienced perioperative hypotension. The median duration of hypotension for each patient was 8.0 [interquartile range, 3.1-23.3] minutes. Reduced cardiac output was present during 77% of the hypotension duration. Patients suffering from postoperative myocardial or acute kidney injury displayed longer duration and more extensive exposure in all hypotension subtypes. However, the percentage of different hypotension subtypes did not differ in patients with or without postoperative myocardial or acute kidney injury. Conclusion: Perioperative hypotension was frequently accompanied by cardiac output reduction in moderate-to-high-risk noncardiac surgical patients. However, due to the pilot nature of this study, the relationship between hypotension subtypes and postoperative myocardial or acute kidney injury still needs further exploration. Clinical trial registration: https://www.chictr.org.cn/showprojEN.html?proj=134260, CTR2200055929.

Suppression of OGN in lung myofibroblasts attenuates pulmonary fibrosis by inhibiting integrin αv-mediated TGF-ß/Smad pathway activation.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) represents a severe and progressive manifestation of idiopathic interstitial pneumonia marked by an uncertain etiology along with an unfavorable prognosis. Osteoglycin (OGN), belonging to the small leucine-rich proteoglycans family, assumes pivotal functions in both tissue formation and damage response. However, the roles and potential mechanisms of OGN in the context of lung fibrosis remain unexplored. METHODS: The assessment of OGN expression levels in fibrotic lungs was conducted across various experimental lung fibrosis mouse models. To elucidate the effects of OGN on the differentiation of lung myofibroblasts, both OGN knockdown and OGN overexpression were employed in vitro. The expression of integrin αv, along with its colocalization with lysosomes and latency-associated peptide (LAP), was monitored in OGN-knockdown lung myofibroblasts. Furthermore, the role of OGN in lung fibrosis was investigated through OGN knockdown utilizing adeno-related virus serotype 6 (AAV6)-mediated delivery. RESULTS: OGN exhibited upregulation in both lungs and myofibroblasts across diverse lung fibrosis mouse models. And laboratory experiments in vitro demonstrated that OGN knockdown inhibited the TGF-ß/Smad signaling pathway in lung myofibroblasts. Conversely, OGN overexpression promoted TGF-ß/Smad pathway in these cells. Mechanistic insights revealed that OGN knockdown facilitated lysosome-mediated degradation of integrin αv while inhibiting its binding to latency-associated peptide (LAP). Remarkably, AAV6-targeted OGN knockdown ameliorated the extent of lung fibrosis in experimental mouse models. CONCLUSION: Our results indicate that inhibiting OGN signaling could serve as a promising therapeutic way for lung fibrosis.

Study of the mechanical properties and propagation mechanisms of non-coplanar and discontinuous joints via numerical simulation experiments.

Non-coplanar and discontinuously jointed rock masses are more complex than coplanar and discontinuously jointed rock masses. The mechanical properties and propagation mechanisms of non-coplanar and discontinuous joints were studied via direct shear tests with microscopic numerical simulation experiments. The numerical simulation tests were performed under different normal stresses, joint inclination angles, and shear rates. The numerical experimental results show that the microscale failure of non-coplanar and discontinuously jointed rock masses is mainly caused by tensile cracks. Additionally, when the peak shear stress is reached, the growth rate of cracks increases rapidly, and the number of cracks increases with increasing normal stress. The shear strength of non-coplanar and discontinuously jointed rock masses increases with increasing normal stress. Under the same normal stress, the variation curves of the shear strength of non-coplanar and discontinuously jointed rock masses with respect to the dip angle exhibit an "S"-shaped nonlinear pattern. Rock masses with joint inclination angles of approximately 15° and 65° have minimum and maximum shear strengths, respectively. The joint dip angle has a significant impact on the final failure mode of rock bridges in the rock mass. As the joint dip angle increases, the final failure modes of rock bridges change from "end-to-end" connection to a combination of "head-to-head" and "tail-to-tail" connections. The shear rate has a certain impact on the peak shear stress, but the impact is not significant. The spatial distribution of the tensile force chains changes as shearing progresses, and stress concentration occurs at the tips of the original joints, which is the reason for the development of long tensile cracks in the deeper parts.

A biosensor method based on surfactant-mediated surface droplet evaporation for the detection of Aflatoxin B1.

Aflatoxin B1 (AFB1) is a common mycotoxin that is of significant global concern due to its impact on food safety. Herein, we innovatively develop a sensing platform to detect AFB1 based on evaporation of surfactant solutions on the hydrophobic surface, resulting in dried patterns with varied sizes. The surfactant CTAB solution produces a relatively large dried pattern due to the surface wetting. However, the reduction in the dried pattern size is found when the mixture of CTAB and AFB1 aptamer is tested, because the formation of CTAB/aptamer complex. Moreover, the dried pattern size of the mixture of CTAB, aptamer, and AFB1 increases due to the specific binding of AFB1 to its aptamer. Using this innovative strategy, the AFB1 detection can be fulfilled with a detection limit of 0.77 pg/mL. As a simple, convenient, inexpensive, and label-free method, the surfactant-mediated surface droplet evaporation-based biosensor is very promising for various potential applications.

The Causal Associations between Adipokines and Alzheimer's Disease: A Two-Sample Mendelian Randomization Study.

Background: Observational studies have indicated the association of alteration of adipokines with Alzheimer's disease (AD). However, it remains unclear whether the associations are causal. Objective: To determine the causal associations between adipokines and AD. Methods: A Mendelian randomization (MR) method was applied to investigate the causal relationships of adipokines, including adiponectin and resistin, with risk of AD. Genetic proxies from genome-wide association studies (GWAS) of adiponectin and resistin were selected as instrumental variables. GWAS summary statistics for AD were extracted as outcome. Results: In this study, we found evidence of the causal effects of adiponectin on AD (OR: 0.850, 95% CI: 0.731-0.990, p = 0.037). However, no relationship between resistin and AD (OR: 0.936, 95% CI: 0.851-1.029, p = 0.171) was detected. In the reverse causation analysis, null associations of AD were found for adiponectin and resistin (all p > 0.05). Conclusions: This study provides evidence of causality between adiponectin and risk of AD. However, no genetic susceptibility of resistin was discovered for AD.

Activation of glutamatergic neurones in the pedunculopontine tegmental nucleus promotes cortical activation and behavioural emergence from sevoflurane-induced unconsciousness in mice.

BACKGROUND: The neural mechanisms underlying sevoflurane-induced loss of consciousness and recovery of consciousness after anaesthesia remain unknown. We investigated whether glutamatergic pedunculopontine tegmental nucleus (PPT) neurones are involved in the regulation of states of consciousness under sevoflurane anaesthesia. METHODS: In vivo fibre photometry combined with electroencephalography (EEG)/electromyography recording was used to record changes in the activity of glutamatergic PPT neurones under sevoflurane anaesthesia. Chemogenetic and cortical EEG recordings were used to explore their roles in the induction of and emergence from sevoflurane anaesthesia. Optogenetic methods combined with EEG recordings were used to explore the roles of glutamatergic PPT neurones and of the PPT-ventral tegmental area pathway in maintenance of anaesthesia. RESULTS: The population activity of glutamatergic PPT neurones was reduced before sevoflurane-induced loss of righting reflex and gradually recovered after return of righting reflex. Chemogenetic inhibition of glutamatergic PPT neurones accelerated induction of anaesthesia (hM4Di-CNO vs mCherry-CNO, 76 [17] vs 121 [27] s, P<0.0001) and delayed emergence from sevoflurane anaesthesia (278 [98] vs 145 [53] s, P<0.0001) but increased sevoflurane sensitivity. Optogenetic stimulation of glutamatergic PPT neurons or of the PPT-ventral tegmental area pathway promoted cortical activation and behavioural emergence during steady-state sevoflurane anaesthesia, reduced the depth of anaesthesia, and caused cortical arousal during sevoflurane-induced EEG burst suppression. CONCLUSIONS: Glutamatergic PPT neurones regulate induction and emergence of sevoflurane anaesthesia.

ProQ binding to small RNA RyfA promotes virulence and biofilm formation in avian pathogenic Escherichia coli.

Avian pathogenic Escherichia coli (APEC) is a notable subpathotype of the nonhuman extraintestinal pathogenic E. coli (ExPEC). Recognized as an extraintestinal foodborne pathogen, the zoonotic potential of APEC/ExPEC allows for cross-host transmission via APEC-contaminated poultry meat and eggs. ProQ, an RNA binding protein, is evolutionarily conserved in E. coli. However, its regulatory roles in the biofilm formation and virulence of APEC/ExPEC have not been explored. In this study, proQ deletion in the APEC strain FY26 significantly compromised its biofilm-forming ability. Furthermore, animal tests and cellular infection experiments showed that ProQ depletion significantly attenuated APEC virulence, thereby diminishing its capacity for bloodstream infection and effective adherence to and persistence within host cells. Transcriptome analysis revealed a decrease in the transcription level of the small RNA (sRNA) RyfA in the mutant FY26ΔproQ, suggesting a direct interaction between the sRNA RyfA and ProQ. This interaction might indicate that sRNA RyfA is a novel ProQ-associated sRNA. Moreover, the direct binding of ProQ to the sRNA RyfA was crucial for APEC biofilm formation, pathogenicity, adhesion, and intracellular survival. In conclusion, our findings provide detailed insight into the interaction between ProQ and sRNA RyfA and deepen our understanding of the regulatory elements that dictate APEC virulence and biofilm development. Such insights are instrumental in developing strategies to counteract APEC colonization within hosts and impede APEC biofilm establishment on food surfaces.

Extracellular vesicles produced by avian pathogenic Escherichia coli (APEC) activate macrophage proinflammatory response and neutrophil extracellular trap (NET) formation through TLR4 signaling.

BACKGROUND: Avian pathogenic Escherichia coli (APEC) is the major pathogen causing important avian diseases in poultry. As an important subtype of extraintestinal pathogenic E. coli, APEC has zoonotic potential and is considered a foodborne pathogen. APEC extracellular vesicles (EVs) may play vital roles in the interaction of the pathogen with its host cells. However, the precise roles played by APEC EVs are still not completely clear, especially in immune cells. RESULTS: In this study, we investigated the relationships between APEC EVs and immune cells. The production and characteristics of the EVs of APEC isolate CT265 were identified. Toll like receptor 4 (TLR4) triggered the cellular immune responses when it interacted with APEC EVs. APEC EVs induced a significant release of proinflammatory cytokines in THP-1 macrophages. APEC EVs induced the macrophage inflammatory response via the TLR4/MYD88/NF-κB signaling pathway, which participated in the activation of the APEC-EV-induced NLRP3 inflammasome. However, the loss of lipopolysaccharide (LPS) from APEC EVs reduced the activation of the NLRP3 inflammasome mediated by TLR4/MYD88/NF-κB signaling. Because APEC EVs activated the macrophage inflammatory response and cytokines release, we speculated that the interaction between APEC EVs and macrophages activated and promoted neutrophil migration during APEC extraintestinal infection. This study is the first to report that APEC EVs induce the formation of neutrophil extracellular traps (NETs) and chicken heterophil extracellular traps. Treatment with APEC EVs induced SAPK/JNK activation in neutrophils. The inhibition of TLR4 signaling suppressed APEC-EV-induced NET formation. However, although APEC EVs activated the immune response of macrophages and initiated NET formation, they also damaged macrophages, causing their apoptosis. The loss of LPS from APEC EVs did not prevent this process. CONCLUSION: APEC-derived EVs induced inflammatory responses in macrophages and NETs in neutrophils, and that TLR4 was involved in the APEC-EV-activated inflammatory response. These findings provided a basis for the further study of APEC pathogenesis.

Dexmedetomidine alleviates pulmonary fibrosis through the ADORA2B-Mediated MAPK signaling pathway.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronically progressive fibrotic pulmonary disease characterized by an uncertain etiology, a poor prognosis, and a paucity of efficacious treatment options. Dexmedetomidine (Dex), an anesthetic-sparing alpha-2 adrenoceptor (α2AR) agonist, plays a crucial role in organ injury and fibrosis. However, the underlying mechanisms of IPF remain unknown. METHODS: In our study, the role of Dex in murine pulmonary fibrosis models was determined by Dex injection intraperitoneally in vivo. Fibroblast activation and myofibroblast differentiation were assessed after Dex treatment in vitro. The activation of MAPK pathway and the expression of Adenosine A2B receptor (ADORA2B) were examined in lung myofibroblasts. Moreover, the role of ADORA2B in Dex suppressing myofibroblast differentiation and pulmonary fibrosis was determined using the ADORA2B agonist BAY60-6583. RESULTS: The results revealed that Dex could inhibit Bleo-induced pulmonary fibrosis in mice. In vitro studies revealed that Dex suppressed TGF-ß-mediated MAPK pathway activation and myofibroblast differentiation. Furthermore, Dex inhibits myofibroblast differentiation and pulmonary fibrosis via downregulating ADORA2B expression. CONCLUSIONS: Our findings suggest Dex as a potential therapeutic agent for pulmonary fibrosis. Dex may alleviate lung fibrosis and myofibroblast differentiation through the ADORA2B-mediated MAPK signaling pathway.

Identification of diagnostic hub genes related to neutrophils and infiltrating immune cell alterations in idiopathic pulmonary fibrosis.

Background: There is still a lack of specific indicators to diagnose idiopathic pulmonary fibrosis (IPF). And the role of immune responses in IPF is elusive. In this study, we aimed to identify hub genes for diagnosing IPF and to explore the immune microenvironment in IPF. Methods: We identified differentially expressed genes (DEGs) between IPF and control lung samples using the GEO database. Combining LASSO regression and SVM-RFE machine learning algorithms, we identified hub genes. Their differential expression were further validated in bleomycin-induced pulmonary fibrosis model mice and a meta-GEO cohort consisting of five merged GEO datasets. Then, we used the hub genes to construct a diagnostic model. All GEO datasets met the inclusion criteria, and verification methods, including ROC curve analysis, calibration curve (CC) analysis, decision curve analysis (DCA) and clinical impact curve (CIC) analysis, were performed to validate the reliability of the model. Through the Cell Type Identification by Estimating Relative Subsets of RNA Transcripts algorithm (CIBERSORT), we analyzed the correlations between infiltrating immune cells and hub genes and the changes in diverse infiltrating immune cells in IPF. Results: A total of 412 DEGs were identified between IPF and healthy control samples, of which 283 were upregulated and 129 were downregulated. Through machine learning, three hub genes (ASPN, SFRP2, SLCO4A1) were screened. We confirmed their differential expression using pulmonary fibrosis model mice evaluated by qPCR, western blotting and immunofluorescence staining and analysis of the meta-GEO cohort. There was a strong correlation between the expression of the three hub genes and neutrophils. Then, we constructed a diagnostic model for diagnosing IPF. The areas under the curve were 1.000 and 0.962 for the training and validation cohorts, respectively. The analysis of other external validation cohorts, as well as the CC analysis, DCA, and CIC analysis, also demonstrated strong agreement. There was also a significant correlation between IPF and infiltrating immune cells. The frequencies of most infiltrating immune cells involved in activating adaptive immune responses were increased in IPF, and a majority of innate immune cells showed reduced frequencies. Conclusion: Our study demonstrated that three hub genes (ASPN, SFRP2, SLCO4A1) were associated with neutrophils, and the model constructed with these genes showed good diagnostic value in IPF. There was a significant correlation between IPF and infiltrating immune cells, indicating the potential role of immune regulation in the pathological process of IPF.

Neutrophil-Related Gene Expression Signatures in Idiopathic Pulmonary Fibrosis: Implications for Disease Characteristic and Identification of Diagnostic Hub Genes.

Background: Idiopathic pulmonary fibrosis (IPF) is a disease with unclear etiology and a poor prognosis. Although the involvement of neutrophils in IPF pathogenesis has been suggested, the exact nature of this relationship remains unclear. Methods: We analyzed data from the Gene Expression Omnibus (GEO) using immune infiltration analysis, weighted gene co-expression network analysis (WGCNA), and consensus cluster analysis. Neutrophil-related genes and hub genes related to neutrophils were identified and differentially expressed between IPF patients and healthy controls. We also validated the expression differences of hub genes in a bleomycin-induced mice model. Results: Immune infiltration analysis revealed a significantly decreased percentage of neutrophils in the lung tissue of IPF patients compared with healthy controls (P<0.001) in both the train and validation sets. Neutrophil-related genes in IPF were identified by WGCNA, and functional enrichment analysis showed that these genes were mainly involved in the cytokine-cytokine receptor interaction pathway and correlated with lung disease, consistent with DEGs between IPF and healthy controls. Eight hub genes related to neutrophils were identified, including MMP16, ARG1, IL1R2, PROK2, MS4A2, PIR, and ZNF436. Consensus cluster analysis revealed a low neutrophil-infiltrating cluster that was correlated with IPF (P<0.001), and a principal component analysis-generated score could distinguish IPF patients from healthy controls, with an area under the curve of 0.930 in the train set and 0.768 in the validation set. We also constructed a diagnostic model using hub genes related to neutrophils, which showed a reliable diagnostic value with an area under the curve of 0.955 in the train set and 0.995 in the validation set. Conclusion: Our findings provide evidence of a low neutrophil-infiltrating characteristic in the IPF microenvironment and identify hub genes related to neutrophils that may serve as diagnostic biomarkers for the disease.

Predicting effects of career adaptability and educational identity on the career decision-making of Chinese higher vocational students.

The present study aimed to explore factors affecting Chinese higher vocational students' career decision-making. A sample (N = 983) was surveyed with a questionnaire. The results showed that somewhat more than half of the students (57.4%) decided to apply for a bachelor's degree whereas the rest decided to work (22.4%) or undecided (20.2%). Academic performance, grade, gender, study major, and career adaptability were shown to predict decision-making. By contrast, educational identity did not predict participants' career decision-making. These findings imply that career education should be based on students' choices for future development.

Prédiction des effets de l'adaptabilité professionnelle et de l'identité éducative sur la prise de décision professionnelle des étudiants professionnels supérieurs chinois. La présente étude visait à explorer les facteurs qui influent sur les décisions de carrière des étudiants professionnels chinois de niveau supérieur. Un échantillon (N = 983) a été sondé au moyen d'un questionnaire. Les résultats ont montré qu'un peu plus de la moitié des étudiants (57,4%) ont décidé de demander une licence, tandis que le reste a décidé de travailler (22,4%) ou indécis (20,2%). Le rendement scolaire, la note, le sexe, les études majeures et l'adaptabilité à la carrière ont permis de prédire la prise de décisions. En revanche, l'identité éducative n'a pas prédit la prise de décisions professionnelles des participants. Ces résultats impliquent que la formation professionnelle devrait être basée sur les choix des étudiants pour leur développement futur.

Predicción de los efectos de la adaptabilidad profesional y la identidad educativa en la toma de decisiones sobre la carrera de los estudiantes de formación profesional superior chinos. El objetivo del presente estudio es explorar los factores que afectan a la toma de decisiones sobre la carrera profesional de los estudiantes chinos. Se encuestó una muestra (N = 983) con un cuestionario. Los resultados mostraron que algo más de la mitad de los estudiantes (57,4%) decidieron solicitar una licenciatura, mientras que el resto decidió trabajar (22,4%) o indeciso (20,2%). Se demostró que el rendimiento académico, la calificación, el género, la especialización y la adaptabilidad profesional predecían la toma de decisiones. Por el contrario, la identidad educativa no predijo la toma de decisiones profesionales de los participantes. Estos hallazgos implican que la educación profesional debe basarse en las opciones de los estudiantes para el desarrollo futuro.

Dietary supplementation with a complex of cinnamaldehyde, carvacrol, and thymol negatively affects the intestinal function in LPS-challenged piglets.

Background: The effects of cinnamaldehyde, carvacrol and thymol complex (CCT) on the growth performance and intestinal function of piglets challenged with lipopolysaccharide (LPS) were determined. Colistin sulphate (CS) was as a positive control. Method: Piglets (n = 24, 32 days of age) were allocated to four treatments: Control group (fed basal diet), LPS group (fed basal diet), CS+LPS group (fed basal diet + 50 mg/kg CS), and CCT+LPS group (fed basal diet + 50 mg/kg CCT). Results: Results showed that diarrhea rates of piglets were significantly reduced by CCT and CS supplementation respectively. Further research showed that CS supplementation tended to improve the intestinal absorption function in LPS-challenged piglets. Moreover, CS supplementation significantly reduced the contents of cortisol in blood and malondialdehyde in the duodenum and the activities of inducible nitric oxide synthase in the duodenum and ileum and total nitric oxide synthase in the ileum in LPS-challenged piglets. CS supplementation significantly increased the activities of sucrase in the ileum and myeloperoxidase in the jejunum in LPS-challenged piglets. CS supplementation significantly alleviated the reduced mRNA levels of immune-related genes (IL-4, IL-6, IL-8, IL-10) in mesenteric lymph nodes and jejunum and mucosal growth-related genes (IGF-1, mTOR, ALP) in LPS-challenged piglets. These results suggested that CS supplementation improved the intestinal function in LPS-challenged piglets by improving intestinal oxidative stress, immune stress, and absorption and repair function. However, although CCT supplementation improved oxidative stress by reducing (p < 0.05) the content of malondialdehyde and the activity of nitric oxide synthase in the duodenum, CCT supplementation tended to aggravate the intestinal absorption dysfunction in LPS-challenged piglets. Furthermore, compared with the control and LPS groups, CCT supplementation remarkably elevated the content of prostaglandin in plasma and the mRNA levels of pro-inflammatory factor IL-6 in mesenteric lymph nodes and jejunum, and reduced the activity of maltase in the ileum in LPS-challenged piglets. These results suggested that CCT supplementation had a negative effect on intestinal function by altering intestinal immune stress response and reducing disaccharidase activity in LPS-challenged piglets. Conclusions: Compared to CS, CCT supplementation exhibited a negative effect on intestinal function, suggesting whether CCT can be as an effective feed additive still needs further study.

Amides as modifiable directing groups in electrophilic borylation.

Amide directed C-H borylation using ≥two equiv. of BBr3 forms borenium cations containing a R2N(R')C[double bond, length as m-dash]O→B(Ar)Br unit which has significant Lewis acidity at the carbonyl carbon. This enables reduction of the amide unit to an amine using hydrosilanes. This approach can be applied sequentially in a one-pot electrophilic borylation-reduction process, which for phenyl-acetylamides generates ortho borylated compounds that can be directly oxidised to the 2-(2-aminoethyl)-phenol. Other substrates amenable to the C-H borylation-reduction sequence include mono and diamino-arenes and carbazoles. This represents a simple method to make borylated molecules that would be convoluted to access otherwise (e.g. N-octyl-1-BPin-carbazole). Substituent variation is tolerated at boron as well as in the amide unit, with diarylborenium cations also amenable to reduction. This enables a double C-H borylation-reduction-hydrolysis sequence to access B,N-polycyclic aromatic hydrocarbons (PAHs), including an example where both the boron and nitrogen centres contain functionalisable handles (N-H and B-OH). This method is therefore a useful addition to the metal-free borylation toolbox for accessing useful intermediates (ArylBPin) and novel B,N-PAHs.

DACT2 protects against pulmonary fibrosis via suppressing glycolysis in lung myofibroblasts.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fibrotic lung disease with poor prognosis and few treatment options. Dapper homolog 2 (DACT2), a member of the DACT gene family, plays crucial roles in tissue development and injury. However, its functions and molecular mechanisms in IPF remain largely unknown. We aimed to investigate the role of DACT2 in the development of pulmonary fibrosis and the therapeutic potential of targeting DACT2 related signaling pathways. METHODS: In our study, adeno-associated virus serotype 6 (AAV6)-mediated DACT2 overexpression was assessed in several mice models of experimental pulmonary fibrosis in vivo. The role of DACT2 in lung myofibroblast differentiation was determined by DACT2 overexpression in vitro. The glucose uptake, extracellular acidification rate, intracellular adenosine-triphosphate (ATP) level and lactate levels of myofibroblasts were detected after DACT2 overexpression. The LDHA degradation rate and colocalization with lysosomes were monitored as well. RESULTS: Intratracheal administration of AAV6-mediated DACT2 overexpression apparently attenuated pulmonary fibrosis in experimental pulmonary fibrosis models. In vitro experiments revealed that DACT2 inhibited TGF-ß-induced myofibroblast differentiation by promoting lysosome-mediated LDHA degradation and thus suppressing glycolysis in myofibroblasts. CONCLUSION: In conclusion, our findings support for DACT2 as a novel pharmacological target for pulmonary fibrosis treatments.

Nongenetic and genetic predictors of haemodynamic instability induced by propofol and opioids: A retrospective clinical study.

AIM: Propofol and opioids are commonly used in anaesthesia, but are highly susceptible to haemodynamic instability, thereby threatening the patient's surgical safety and prognosis. The purpose of this study was to investigate the predictors of haemodynamic instability and establish its predictive model. METHODS: A total of 150 Chinese patients undergoing thyroid or breast surgery participated in the study, with target-controlled infusion concentrations of propofol, opioids dosage, heart rate (HR), mean arterial pressure (MAP) and Narcotrend Index recorded at key points throughout the procedure. The Agena MassARRAY system was used to genotype candidate single nucleotide polymorphisms related to pharmacodynamics and pharmacokinetics of propofol and opioids. RESULTS: Among nongenetic factors, baseline HR (R = -.579, P < .001) and baseline MAP (R = -.725, P < .001) had a significant effect on the haemodynamic instability. Among genetic factors, the CT/CC genotype of GABRB1 rs4694846 (95% confidence interval [CI]: -11.309 to -3.155), AA/AG of OPRM1 rs1799971 (95%CI: 0.773 to 10.290), AA of CES2 rs8192925 (95%CI: 1.842 to 9.090) were associated with higher HR instability; the AA/GG genotype of NR1I2 rs6438550 (95%CI: 0.351 to 7.761), AA of BDNF rs2049046 (95%CI: -9.039 to -0.640) and GG of GABBR2 rs1167768 (95%CI: -10.146 to -1.740) were associated with higher MAP instability. The predictive models of HR and MAP fluctuations were developed, accounting for 45.0 and 59.2% of variations, respectively. CONCLUSION: We found that cardiovascular fundamentals and genetic variants of GABRB1, GABBR2, OPRM1, BDNF, CES2 and NR1I2 are associated with cardiovascular susceptibility, which can provide a reference for haemodynamic management in clinical anaesthesia.

Genomics Analysis to Identify Multiple Genetic Determinants That Drive the Global Transmission of the Pandemic ST95 Lineage of Extraintestinal Pathogenic Escherichia coli (ExPEC).

Extraintestinal pathogenic Escherichia coli (ExPEC) is a pathogen that causes host extraintestinal diseases. The ST95 E. coli lineage is one of the dominant ExPEC lineages in humans and poultry. In this study, we took advantage of extensive E. coli genomes available through public open-access databases to construct a detailed understanding of the phylogeny and evolution of ST95. We used a high variability of accessory genomes to highlight the diversity and dynamic traits of ST95. Isolates from diverse hosts and geographic sources were randomly located on the phylogenetic tree, which suggested that there is no host specificity for ST95. The time-scaled phylogeny showed that ST95 is an ancient and long-lasting lineage. The virulence genes, resistance genes, and pathogenicity islands (PAIs) were characterized in ST95 pan-genomes to provide novel insights into the pathogenicity and multidrug resistance (MDR) genotypes. We found that a pool of large plasmids drives virulence and MDR. Based on the unique genes in the ST95 pan-genome, we designed a novel multiplex PCR reaction to rapidly detect ST95. Overall, our study addressed a gap in the current understanding of ST95 ExPEC genomes, with significant implications for recognizing the success and spread of ST95.

Reductions in bacterial viability stimulate the production of Extra-intestinal Pathogenic Escherichia coli (ExPEC) cytoplasm-carrying Extracellular Vesicles (EVs).

Extra-intestinal Pathogenic Escherichia coli (ExPEC) is defined as an extra-intestinal foodborne pathogen, and several dominant sequence types (STs) ExPEC isolates are highly virulent, with zoonotic potential. Bacteria extracellular vesicles (EVs) carry specific subsets of molecular cargo, which affect various biological processes in bacteria and host. The mechanisms of EVs formation in ExPEC remains to be elucidated. Here, the purified EVs of ExPEC strains of different STs were isolated with ultracentrifugation processes. A comparative analysis of the strain proteomes showed that cytoplasmic proteins accounted for a relatively high proportion of the proteins among ExPEC EVs. The proportion of cytoplasm-carrying vesicles in ExPEC EVs was calculated with a simple green fluorescent protein (GFP) expression method. The RecA/LexA-dependent SOS response is a critical mediator of generation of cytoplasm-carrying EVs. The SOS response activates the expression of prophage-associated endolysins, Epel1, Epel2.1, and Epel2.2, which triggered cell lysis, increasing the production of ExPEC cytoplasm-carrying EVs. The repressor LexA controlled directly the expression of these endolysins by binding to the SOS boxes in the endolysin promoter regions. Reducing bacterial viability stimulated the production of ExPEC EVs, especially cytoplasm-carrying EVs. The imbalance in cell division caused by exposure to H2O2, the deletion of ftsK genes, or t6A synthesis defects activated the RecA/LexA-dependent SOS response, inducing the expression of endolysins, and thus increasing the proportion of cytoplasm-carrying EVs in the total ExPEC EVs. Antibiotics, which decreased bacterial viability, also increase the production of ExPEC cytoplasm-carrying EVs through the SOS response. Changes in the proportion of cytoplasm-carrying EVs affected the total DNA content of ExPEC EVs. When macrophages are exposed to a higher proportion of cytoplasm-carrying vesicles, ExPEC EVs were more cytotoxic to macrophages, accompanied with more-severe mitochondrial disruption and a higher level of induced intrinsic apoptosis. In summary, we offered comprehensive insight into the proteome analysis of ExPEC EVs. This study demonstrated the novel formation mechanisms of E. coli cytoplasm-carrying EVs.

Association of glioma CD44 expression with glial dynamics in the tumour microenvironment and patient prognosis.

Because of the heterogeneity of lower-grade gliomas (LGGs), patients show various survival outcomes that are not reliably predicted by histological classification. The tumour microenvironment (TME) contributes to the initiation and progression of brain LGGs. Identifying potential prognostic markers based on the immune and stromal components in the TME will provide new insights into the dynamic modulation of these two components of the TME in LGGs. We applied ESTIMATE to calculate the ratio of immune and stromal components from The Cancer Genome Atlas database. After combined differential gene expression analysis, protein-protein interaction network construction and survival analysis, CD44 was screened as an independent prognostic factor and subsequently validated utilizing data from the Chinese Glioma Genome Atlas database. To decipher the association of glioma cell CD44 expression with stromal cells in the TME and tumour progression, RT-qPCR, cell viability and wound healing assays were employed to determine whether astrocytes enhance glioma cell viability and migration by upregulating CD44 expression. Surprisingly, M1 macrophages were identified as positively correlated with CD44 expression by CIBERSORT analysis. CD44+ glioma cells were further suggested to interact with microglia-derived macrophages (M1 phenotype) via osteopontin signalling on the basis of single-cell sequencing data. Overall, we found that astrocytes could elevate the CD44 expression level of glioma cells, enhancing the recruitment of M1 macrophages that may promote glioma stemness via osteopontin-CD44 signalling. Thus, glioma CD44 expression might coordinate with glial activities in the TME and serve as a potential therapeutic target and prognostic marker for LGGs.

New insight into the analgesic recipe: A cohort study based on smart patient-controlled analgesia pumps records.

Purpose: Intravenous patient-controlled analgesia (IV-PCA) has been widely used; however, regimen criteria have not yet been established. In China, the most often used opioid is sufentanil, for which repeated doses are a concern, and empirical flurbiprofen axetil (FBP) as an adjuvant. We hypothesized that hydromorphone would be a better choice and also evaluated the effectiveness of FBP as an adjuvant. Methods: This historical cohort study was conducted in two tertiary hospitals in China and included 12,674 patients using hydromorphone or sufentanil for IV-PCA between April 1, 2017, and January 30, 2021. The primary outcome was analgesic insufficiency at static (AIS). The secondary outcomes included analgesic insufficiency with movement (AIM) and common opioid-related adverse effects such as postoperative nausea and vomiting (PONV) and dizziness. Results: Sufentanil, but not the sufentanil-FBP combination, was associated with higher risks of AIS and AIM compared to those for hydromorphone (OR 1.64 [1.23, 2.19], p < 0.001 and OR 1.42 [1.16, 1.73], p < 0.001). Hydromorphone combined with FBP also decreased the risk of both AIS and AIM compared to those for pure hydromorphone (OR 0.74 [0.61, 0.90], p = 0.003 and OR 0.80 [0.71, 0.91], p < 0.001). However, the risk of PONV was higher in patients aged ≤35 years using FBP (hydromorphone-FBP vs. hydromorphone and sufentanil-FBP vs. hydromorphone, OR 1.69 [1.22, 2.33], p = 0.001 and 1.79 [1.12, 2.86], p = 0.015). Conclusion: Hydromorphone was superior to sufentanil for IV-PCA in postoperative analgesia. Adding FBP may improve the analgesic effects of both hydromorphone and sufentanil but was associated with an increased risk of PONV in patients <35 years of age.