Sevoflurane alleviates inflammation, apoptosis and permeability damage of human umbilical vein endothelial cells induced by lipopolysaccharide by inhibiting endoplasmic reticulum stress via upregulating RORα.

Endothelial dysfunction often accompanies sepsis. Sevoflurane (Sev) is a widely used inhaled anesthetic that has a protective effect on sepsis-associated damage. We aimed to elucidate the role of Sev in endothelial dysfunction by using a model of LPS induced HUVECs. Sev increased the viability and decreased the apoptosis of HUVECs exposed to LPS. Inflammation and endothelial cell adhesion were improved after Sev addition. Besides, Sev alleviated LPS-induced endothelial cell permeability damage in HUVECs. RORα served as a potential protein that bound to Sev. Importantly, Sev upregulated RORα expression and inhibited endoplasmic reticulum (ER) stress in LPS-treated HUVECs. RORα silencing reversed the impacts of Sev on ER stress. Moreover, RORα deficiency or tunicamycin (ER stress inducer) treatment restored the effects of Sev on the viability, apoptosis, inflammation and endothelial permeability damage of HUVECs exposed to LPS. Taken together, Sev ameliorated LPS-induced endothelial cell damage by targeting RORα to inhibit ER stress.

A Dual Fluorescence Turn-On Sensor Array Formed by Poly(para-aryleneethynylene) and Aggregation-Induced Emission Fluorophores for Sensitive Multiplexed Bacterial Recognition.

Bacterial infections have emerged as the leading causes of mortality and morbidity worldwide. Herein, we developed a dual-channel fluorescence "turn-on" sensor array, comprising six electrostatic complexes formed from one negatively charged poly(para-aryleneethynylene) (PPE) and six positively charged aggregation-induced emission (AIE) fluorophores. The 6-element array enabled the simultaneous identification of 20 bacteria (OD600=0.005) within 30s (99.0 % accuracy), demonstrating significant advantages over the array constituted by the 7 separate elements that constitute the complexes. Meanwhile, the array realized different mixing ratios and quantitative detection of prevalent bacteria associated with urinary tract infection (UTI). It also excelled in distinguishing six simulated bacteria samples in artificial urine. Remarkably, the limit of detection for E. coli and E. faecalis was notably low, at 0.000295 and 0.000329 (OD600), respectively. Finally, optimized by diverse machine learning algorithms, the designed array achieved 96.7 % accuracy in differentiating UTI clinical samples from healthy individuals using a random forest model, demonstrating the great potential for medical diagnostic applications.

Multilocus Distance-Regulated Sensor Array for Recognition of Polyphenols via Machine Learning and Indicator Displacement Assay.

Developing new strategies to construct sensor arrays that can effectively distinguish multiple natural components with similar structures in mixtures is an exceptionally challenging task. Here, we propose a new multilocus distance-modulated indicator displacement assay (IDA) strategy for constructing a sensor array, incorporating machine learning optimization to identify polyphenols. An 8-element array, comprising two fluorophores and their six dynamic covalent complexes (C1-C6) formed by pairing two fluorophores with three distinct distance-regulated quenchers, has been constructed. Polyphenols with diverse spatial arrangements and combinatorial forms compete with the fluorophores by forming pseudocycles with quenchers within the complexes, leading to varying degrees of fluorescence recovery. The array accurately and effectively distinguished four tea polyphenols and 16 tea varieties, thereby demonstrating the broad applicability of the multilocus distance-modulated IDA array in detecting polyhydroxy foods and natural medicines.

The relationship between professional quality of life and work environment among ICU nurses in Chinese: a cross-sectional study.

Objective: To explore the relationship between the professional quality of life and work environment among intensive care unit nurses, and identify the influencing factors of intensive care unit nurses' professional quality of life. Methods: This study design is cross-sectional and correlational descriptive. Four hundred fourteen intensive care unit nurses from Central China were recruited. Data were collected from three questionnaires of self-designed demographic questions, the professional quality of life scale and the nursing work environment scale. Descriptive statistics, Pearson's correlation, bivariate analysis and multiple linear regression were used to analyze the data. Results: A total of 414 questionnaires was collected, for an effective recovery rate of 98.57%. The original scores of the three sub-scales of professional quality of life were 33.58 ± 6.43, 31.83 ± 5.94, and 32.55 ± 5.74. Compassion satisfaction was positively correlated with the nursing working environment (p < 0.05), job burnout, and secondary trauma were negatively correlated with nursing work in environment (p < 0.05). Multiple linear regression analysis results show that, the nursing working environment entered into the influential factor model of professional quality of life scale (p < 0.001). The nursing working environment independently explained 26.9% of the changes in compassion satisfaction, 27.1% of the changes in job burnout, and 27.5% of the changes in secondary trauma. The nursing work environment is an important factor affecting the professional quality of life. Conclusion: The better the nursing working environment, the higher the professional quality of life of intensive care unit nurses. Decision makers and managers can focus on improving the working environment of nurses, which may be a new perspective for managers to improve the professional quality of life of nurses and stabilize the nursing team.

Gut microbiome alterations in ICU patients with enteral nutrition-related diarrhea.

Enteral Nutrition-related Diarrhea (END) is an extremely common complication in Intensive Care Unit (ICU) patients. However, it is currently unclear whether the patient's gut microbiota is disturbed. Our study aimed to explore the characteristics of gut microbiota changes in END patients. We divided ICU patients into no-END group (n = 7) and END group (n = 7) according to whether they had END, then stool samples were collected separately. The V3-V4 region of stool bacterial 16S rRNA gene was amplified by PCR and sequenced on an Illumina MiSeq PE300 platform. Microbiome data obtained by quality control were analyzed, including microbial community composition, diversity and gene function prediction.The results showed that the dominant gut microbiota in ICU patients who were given total enteral nutrition were Firmicutes, Proteobacteria, Bacteroidetes, Actinobacteria, and Verrucomicrobia. Bacterial richness and diversity in END patients were all significantly lower than those in no-END patients. In addition, END caused significant changes in bacterial composition. LEfSe found 34 biomarkers represented by Bacteroidetes and Subdoligranulum in the no-END group as well as 11 biomarkers represented by Enterococcus and Klebsiella in the END group. Finally, through PICRUST function prediction, we found that diarrhea led to abnormal changes in numerous KEGG pathways mainly related to immunity and metabolism. In short, ICU patients with END have severe gut dysbiosis, and our study provides a reliable experimental basis for the patient's microbiota therapy.

A Multichannel Fluorescent Tongue for Amyloid-ß Aggregates Detection.

Attention has been paid to the early diagnosis of Alzheimer's disease, due to the maximum benefit acquired from the early-stage intervention and treatment. However, the sensing techniques primarily depended upon for neuroimaging and immunological assays for the detection of AD biomarkers are expensive, time-consuming and instrument dependent. Here, we developed a multichannel fluorescent tongue consisting of four fluorescent dyes and GO through electrostatic and π-π interaction. The array distinguished multiple aggregation states of 1 µM Aß40/Aß42 with 100% prediction accuracy via 10-channel signal outputs, illustrating the rationality of the array design. Screening vital sensor elements for the simplified sensor array and the optimization of sensing system was achieved by machine learning algorithms. Moreover, our sensing tongue was able to detect the aggregation states of Aß40/Aß42 in serum, demonstrating the great potential of multichannel array in diagnosing the Alzheimer's diseases.

Knowledge, attitudes and practices of ICU nurses regarding subsyndromal delirium among 20 hospitals in China: a descriptive cross-sectional survey.

OBJECTIVES: This study sought to investigate nurses' knowledge, attitudes and practices, and analyse the influencing factors for subsyndromal delirium (SSD). DESIGN: A descriptive cross-sectional survey. SETTING: E-questionnaires were distributed to intensive care unit (ICU) nurses from 20 tertiary-grade, A-class hospitals in Henan Province, China. PARTICIPANTS: A total of 740 ICU nurses participated in the questionnaire survey. MAIN OUTCOME MEASURES: Each dimension score is converted to a percentage scale. A score of ≤60% on each dimension of the questionnaire was considered a negative score, <80% was considered a intermediate score and ≥80% was considered an excellent score. RESULTS: A total of 733 questionnaires were included in the study. More than half of the nurses were at the intermediate level, and a few nurses were at the excellent level. Nurses self-assessed their level of knowledge was intermediate. In the attitudes dimension, nurses' attitudes were negative. The results of the practical dimension showed that most nurses could carry out the clinical practice. Multiple linear regression analysis showed that educational level and received SSD training were influencing factors. CONCLUSIONS: ICU nursing staff overestimated their knowledge of SSD and showed a negative attitude towards it. Various forms of education and training are necessary.

Machine Learning-Assisted Sensor Array Based on Poly(amidoamine) (PAMAM) Dendrimers for Diagnosing Alzheimer's Disease.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, and the early diagnosis of AD remains challenging. Here we have developed a fluorescent sensor array composed of three modified polyamidoamine dendrimers. Proteins of various properties were differentiated via this array with 100% accuracy, proving the rationality of the array's design. The mechanism of the fluorescence response was discussed. Furthermore, the robust three-element array enables parallel detection of multiple Aß40/Aß42 aggregates (0.5 µM) in diverse interferents, serum media, and cerebrospinal fluid (CSF) with high accuracy, through machine learning algorithms, demonstrating the tremendous potential of the sensor array in Alzheimer's disease diagnosis.

SNP screening of the MSTN gene and correlation analysis between genetic polymorphisms and growth traits in Dazu black goat.

The aim of this study was to detect SNPs in myostatin (MSTN) gene of four goat breeds, and analyze the correlation of these markers on body measurement traits in the Dazu black goat breed. In total, twenty polymorphic sites were found in one hundred forty-eight individuals, and all SNPs were distributed in introns 1 and 2, except g. 425 C > T, which was found in the regulatory region. Three SNPs (g. 2732 C > T, g. 2752 G > A and g. 4552 A > C) were polymorphic in all four breeds. None of the tag SNPs (g. 425 C > T, g. 1583 A > G, 2732 C > T, g. 4552 A > C and g. 5167 C > T) were significantly correlated with body measurement traits (p > 0.05) in the Dazu black goat. However, individuals with genotype combination 3 (GtC 3) of tag SNPs had higher birth weight and weaning weight than individuals with the other genotype combinations (p < 0.05). Moreover, the genotype combination 4 (GtC 4) was significantly associated with body length and height at the age of 2 months (p < 0.05), and genotype combination 13 (GtC 13) was significantly correlated with body height at 6 months (p < 0.05). Briefly, the combined tag SNP markers might be useful for goat marker-associated selective breeding.

Synthesis and Structure-Activity Relationship Studies of N-monosubstituted Aroylthioureas as Urease Inhibitors.

BACKGROUND: Thiourea is a classical urease inhibitor which is usually used as a positive control, and many N,N'-disubstituted thioureas have been determined as urease inhibitors. However, due to steric hindrance, N,N'-disubstituted thiourea motif could not bind urease as thiourea. On the contrary, N-monosubstituted thiourea with a tiny thiourea motif could theoretically bind into the active pocket as thiourea. OBJECTIVE: A series of N-monosubstituted aroylthioureas were designed and synthesized for evaluation as urease inhibitors. METHODS: Urease inhibition was determined by the indophenol method and IC50 values were calculated using computerized linear regression analysis of quantal log dose-probit functions. The kinetic parameters were estimated via surface plasmon resonance (SPR) and by nonlinear regression analysis based on the mixed type inhibition model derived from Michaelis-Menten kinetics. RESULTS: Compounds b2, b11, and b19 reversibly inhibited urease with a mixed mechanism, and showed excellent potency against both cell-free urease and urease in the intact cell, with IC50 values being 90- to 450-fold and 5- to 50-fold lower than the positive control acetohydroxamic acid, respectively. The most potent compound b11 showed an IC50 value of 0.060 ± 0.004µM against cell-free urease, which bound to urea binding site with a very low KD value (0.420±0.003nM) and a very long residence time (6.7 min). Compound b11 was also demonstrated to have very low cytotoxicity to mammalian cells. CONCLUSION: The results revealed that N-monosubstituted aroylthioureas bound to the active site of urease as expected, and represent a new class of urease inhibitors for the development of potential therapeutics against infections caused by urease-containing pathogens.

N-monosubstituted thiosemicarbazide as novel Ure inhibitors: synthesis, biological evaluation and molecular docking.

Background: Identification of novel Ure inhibitors with high potency has received considerable attention. Methodology & results: Ure inhibition was determined using the indophenol method, the affinities to Ure were estimated via surface plasmon resonance. Seventeen new plus ten known N-monosubstituted thiosemicarbazides were synthesized and identified as novel Ure inhibitors. Out of these compounds, compound b5 shows excellent activity against both crude Ure from Helicobacter pylori (IC50 = 0.04 µM) and Ure in living cell (IC50 = 0.27 µM), with the potency being over 600-fold higher than clinical used drug acetohyroxamic acid, respectively. Surface plasmon resonance demonstrated the high affinity (Kd.#x00A0;= 6.32 nM) of b5 to Ure. Conclusion: This work provides a class of novel and promising Ure inhibitors.

SNP of AHSA2 gene in three cattle breeds using snapshot technology.

Droughtmaster is a tropical breed of beef cattle that can survive in hot climates and easily adapt to torrid environments. These traits are important in livestock breeding. In this study, we genotyped five single-nucleotide polymorphisms (SNPs) of the AHSA2 gene from 190 cattle belonging to three different breeds (Droughtmaster, Angus and Simmental) by using snapshot technology. This work aimed to identify the valuable molecular marker of heat resistance in cattle. Results showed that Droughtmaster exhibited higher expected heterozygosity and polymorphic information content compared with the two other breeds. The AHSA2-1 locus deviated from the Hardy-Weinberg equilibrium in the Droughtmaster breed (P < 0.05). Two SNPs in Droughtmaster diverged significantly from Angus and Simmental. The SNPs were identified as AHSA2-3 and AHSA2-4, which were closely linked to the three breeds based on pair-wise FST. AHSA2-4 involved a missense mutation. In summary, the GG genotypes in AHSA2-3 and AHSA2-4 may be candidate genotypes associated with heat resistance traits and may serve as valuable genetic markers for breeding of heat-tolerant beef cattle in the future.

N-monoarylacetothioureas as potent urease inhibitors: synthesis, SAR, and biological evaluation.

A urease inhibitor with good in vivo profile is considered as an alternative agent for treating infections caused by urease-producing bacteria such as Helicobacter pylori. Here, we report a series of N-monosubstituted thioureas, which act as effective urease inhibitors with very low cytotoxicity. One compound (b19) was evaluated in detail and shows promising features for further development as an agent to treat H. pylori caused diseases. Excellent values for the inhibition of b19 against both extracted urease and urease in intact cell were observed, which shows IC50 values of 0.16 ± 0.05 and 3.86 ± 0.10 µM, being 170- and 44-fold more potent than the clinically used drug AHA, respectively. Docking simulations suggested that the monosubstituted thiourea moiety penetrates urea binding site. In addition, b19 is a rapid and reversible urease inhibitor, and displays nM affinity to urease with very slow dissociation (koff=1.60 × 10-3 s-1) from the catalytic domain.

Effect of cinnamon essential oil on gut microbiota in the mouse model of dextran sodium sulfate-induced colitis.

Increasing evidence has confirmed that the antimicrobial and anti-inflammatory effects of cinnamon essential oil (CEO) contribute to protection against inflammatory bowel disease (IBD). The dextran sodium sulfate (DSS)-induced colitis mouse model was established to investigate the correlation between the protective effects of CEO and the regulation of intestinal microflora. The symptoms of IBD were assessed by measuring the hemoglobin content, myeloperoxidase activity, histopathological observation, cytokines, and toll-like receptor (TLR4) expression. The alteration of the fecal microbiome composition was analyzed by 16S rRNA gene sequencing. The results indicated that the oral administration of CEO enriched with cinnamaldehyde effectively alleviated the development of DSS-induced colitis. In contrast to the inability of antibiotics to regulate flora imbalance, the mice fed with CEO had an improved diversity and richness of intestinal microbiota, and a modified community composition with a decrease in Helicobacter and Bacteroides and an increase in Bacteroidales_S24-7 family and short-chain fatty acids (SCFA)-producing bacteria (Alloprevotella and Lachnospiraceae_NK4A136_group). Moreover, the correlation analysis showed that TLR4 and tumor necrosis factor-α was positively correlated with Helicobacter, but inversely correlated with SCFA-producing bacteria. These findings indicated from a new perspective that the inhibitory effect of CEO on IBD was closely related to improving the intestinal flora imbalance.

Immunological characterization of the American cockroach allergen Per a 9 expressed in baculovirus-infected insect cells.

American cockroach (CR) allergy has been recognized as important IgE-mediated type I hypersensitivity. Per a 9 is an arginine kinase, reacting with IgE in sera of all CR allergic Thai patients. Per a 9 gene was cloned and expressed in eukaryotic systems (baculovirus-infected insect cells). The expressed Per a 9 was purified by Nickel column. The antigenicities were analyzed by ELISA, immunoblot analysis and basophile activation test. The results show that 13 out of 16 (81.3%) sera from American CR patients reacted to Per a 9, confirming that Per a 9 is a major allergen of CR. The IgE reactivity of Per a 9 in the sera from American CR patients was increased 8.3-fold in comparison with the sera from healthy controls. Per a 9 at 1.0 µg/ml induced an approximately up to 5.6-fold increase in CD63 and CCR3 double positive cells when incubating with passively sensitized basophils from by sera from American CR patients.

Modulatory effect of Lactobacillus acidophilus KLDS 1.0738 on intestinal short-chain fatty acids metabolism and GPR41/43 expression in ß-lactoglobulin-sensitized mice.

We investigated the correlation between the beneficial effect of Lactobacillus acidophilus on gut microbiota composition, metabolic activities, and reducing cow's milk protein allergy. Mice sensitized with ß-lactoglobulin (ß-Lg) were treated with different doses of L. acidophilus KLDS 1.0738 for 4 weeks, starting 1 week before allergen induction. The results showed that intake of L. acidophilus significantly suppressed the hypersensitivity responses, together with increased fecal microbiota diversity and short-chain fatty acids (SCFAs) concentration (including propionate, butyrate, isobutyrate, and isovalerate) when compared with the allergic group. Moreover, treatment with L. acidophilus induced the expression of SCFAs receptors, G-protein-coupled receptors 41 (GPR41) and 43 (GPR43), in the spleen and colon of the allergic mice. Further analysis revealed that the GPR41 and GPR43 messenger RNA expression both positively correlated with the serum concentrations of transforming growth factor-ß and IFN-γ (p < .05), but negatively with the serum concentrations of IL-17, IL-4, and IL-6 in the L. acidophilus-treated group compared with the allergic group (p < .05). These results suggested that L. acidophilus protected against the development of allergic inflammation by improving the intestinal flora, as well as upregulating SCFAs and their receptors GPR41/43.

Effect of Lactobacillus acidophilus KLDS 1.0738 on miRNA expression in in vitro and in vivo models of ß-lactoglobulin allergy.

This study aims to investigate the correlation between the ability of L. acidophilus to modulate miRNA expression and prevent Th17-dominated ß-lactoglobulin (ß-Lg) allergy. In vitro immunomodulation was evaluated by measuring splenocyte proliferation, Th17-related immune response and miRNA expression in ß-Lg-sensitized splenocytes cultured with live L. acidophilus. Next, the allergic mouse model was used to evaluate anti-allergy capability of lactobacilli. The ß-Lg challenge led to induction of up-regulation of miR-146a, miR-155, miR-21 and miR-9 expression in both in vivo and in vitro, along with increased Th17-related cytokine levels and mRNA expression of RORγt and IL-17. However, treatment of live L. acidophilus significantly suppressed hypersensitivity responses and Th17 cell differentiation. Moreover, administration of live L. acidophilus reduced expression of four miRNAs, especially miR-146a and miR-155. In addition, the decreased expression of the miRNAs in the spleen of the L. acidophilus-treated group was closely associated with decrease of IL-17 and RORγt mRNA expression.

The synthesis and evaluation of phenoxyacylhydroxamic acids as potential agents for Helicobacter pylori infections.

Two series of ω-phenoxy contained acylhydroxamic acids as novel urease inhibitors were designed and synthesized. Biological activity evaluations revealed that ω-phenoxypropinoylhydroxamic acids were more active than phenoxyacetohydroxamic acids. Out of these compounds, 3-(3,4-dichlorophenoxy)propionylhydroxamic acid c24 showed significant potency against urease in both cell free extract (IC50 = 0.061 ±â€¯0.003 µM) and intact cell (IC50 = 0.89 ±â€¯0.05 µM), being over 450- and 120-fold more potent than the clinically prescribed urease inhibitor AHA, repectively. Non-linear fitting of experimental data (V-[S]) suggested a mixed-type inhibition mechanism and a dual site binding mode of these compounds.

Arylamino containing hydroxamic acids as potent urease inhibitors for the treatment of Helicobacter pylori infection.

A novel series of aniline-containing hydroxamic acids were designed, synthesized and evaluated as anti-virulence agents for the treatment of gastritis and gastric ulcer caused by Helicobacter pylori. In vitro enzyme-based screen together with in vivo assays and structure-activity relationship (SAR) studies led to the discovery of three potent urease inhibitors 3-(3,5-dichlorophenylamino)N-hydroxypropanamide (3a), 3-(2-chlorophenylamino)N-hydroxypropanamide (3d) and 3-(2,4-dichlorophenylamino)N-hydroxypropanamide (3n). Compounds 3a, 3d and 3n showed excellent urease inhibition with IC50 values 0.043 ±â€¯0.005, 0.055 ±â€¯0.008 and 0.018 ±â€¯0.002 µM, and significantly depressed gastritis developing at the dose of 32 mg/kg b. i.d with eradication rates of H. pylori reaching 92.3, 84.6 and 100%, respectively. Preliminary safety studies (acute toxicity in mice) disclosed that 3a, 3d and 3n was well-tolerated in KM mice with LD50s of 2982.8, 3349.4 and 3126.9 mg/kg, respectively. Collectively, the data obtained in this study indicate that 3a, 3d and 3n, in particular 3n, could considered as promising candidates for the potential treatment of H. pylori caused gastritis and gastric ulcer, and hence merit further studies.

Resolution and evaluation of 3-chlorophenyl-3-hydroxypropionylhydroxamic acid as antivirulence agent with excellent eradication efficacy in Helicobacter pylori infected mice.

The continuing emergence of drug-resistant Helicobacter pylori (HP) drives the ongoing need for the development of new and effective anti-HP drugs. Urease inhibitor has now gained strong interest as an alternative approach for HP infections. 3-Chlorophenyl-3-hydroxypropionylhydroxamic acid (CPH), a novel urease inhibitor identified in our group, shows impressive potency, which was optically separated for a further exploration. Here, we report in vitro/in vivo pharmacological evaluation of (±)-CPHs and the enantiomers. The raceme and the individual enantiomers significantly suppress gastritis at 32 mg/kg b.i.d dose with lower toxicity to mammalian cells (with CC50s ≥ 3.16 mM) and mice (LD50s ≥ 2338 mg/kg) than the clinically used agent acetohydroxamic acid. Furthermore, a significant increase of eradication of HP is observed for the combination of (±)-CPHs or the enantiomers with an antimicrobial. These studies revealed that CPH is a promising candidate for an alternative treatment of HP-dependent conditions by targeting virulence factor urease, and CPH may be used as a raceme.