UIO66 low background signal and fluorescence synergism strategy for highly sensitive detection of Salmonella typhimurium.

Successful construction of a detection method for Salmonella typhimurium (S. typhimurium) based on the synergy of hybridization chain reaction (HCR) and fluorescence was realized in this paper. First, the aptamer modified with the quenching group Black Hole Quencher-1 acid (BHQ1) was immobilized on the magnetic beads in combination with the complementary chain of the aptamer modified with 6-carboxyfluorescein (6-FAM). Second, S. typhimurium and cDNA-6-FAM immobilized on magnetic beads competitively bound to the aptamer. Finally, the cDNA-6-FAM was released after magnetic separation acted as a promoter to trigger HCR amplification when the target presented. The fluorescence signal could be significantly improved by the combination of green SYBR Green I (SGI) and HCR long double-stranded DNA and the fluorescent synergy of 6-FAM and SGI. Because of the separation of target and its aptamer, the trigger strand was abstracted by magnetic separation. There was no HCR to generate long double-stranded DNA, and the fluorescence of excess hairpin/SGI could be adsorbed through UIO66 so that only a very low background signal was detected. This fluorescent sensor was capable of monitoring S. typhimurium in the range of 10-3.2 × 107 CFU mL-1 with a limit of detection as low as 1.5 CFU mL-1. Because of the excellent properties of the aptasensor and the validity of SGI fluorescence synergy, this HCR enzyme-free amplification strategy could be generalized to other areas.

Synthesis of dual models multivalent activatable aptamers based on HCR and RCA for ultrasensitive detection of Salmonella typhimurium.

Aptamers have superior structural properties and have been widely used in bacterial detection methods. However, the problem of low affinity still exists in complex sample detection. In contrast, hybridization chain reaction (HCR)-based model I and rolling circle amplification (RCA)-based model II multivalent activatable aptamers (multi-Apts) can fulfill the need for low-cost, rapid, highly sensitive and high affinity detection of S. typhimurium. In our research, two models of multi-Apts were designed. First, a monovalent activatable aptamer (mono-Apt) was constructed by fluorescence resonance energy transfer (FRET) with an S. typhimurium aptamer and its complementary chain of BHQ1. Next, the DNA scaffold was obtained by HCR and RCA, and the multi-Apts were obtained by self-assembly of the mono-Apt with a DNA scaffold. In model I, when target was presented, the complementary chain BHQ1 was released due to the binding of multi-Apts to the target and was subsequently adsorbed by UIO66. Finally, a FRET-based fluorescence detection signal was obtained. In mode II, the multi-Apts bound to the target, and the complementary chain BHQ1 was released to become the trigger chain for the next round of amplification of HCR with a fluorescence detection signal. HCR and RCA based multi-Apts were able to detect S. typhimurium as low as 2 CFU mL-1 and 1 CFU mL-1 respectively. Multi-Apts amplification strategy provides a new method for early diagnosis of pathogenic microorganisms in foods.

Erratum: ß-elemene promotes the senescence of glioma cells through regulating YAP-CDK6 signaling.

[This corrects the article on p. 370 in vol. 11, PMID: 33575077.].

Study on the relationship between atrial high-rate episode and left atrial strain in patients with cardiac implantable electronic device.

Background: Although atrial high-rate episode (AHRE) and atrial fibrillation (AF) cannot entirely be identical, recent studies suggest AHRE is linked to AF development and shares some characteristics with AF regarding thromboembolism. At present, there is still lack of predictive indicators for AHRE and diagnostic methods and clinical indicators for AHRE in patients without cardiac implantable electronic device (CIED). The aim of this study was thus to explore the relationship between AHRE and left atrial (LA) strain parameters with the goal of identifying high-risk populations of AHRE by LA strain characteristics. Methods: From February 2022 to May 2023, a total of 105 CIED patients were enrolled and divided into two groups based on whether AHRE had occurred: AHRE (-) group (n=65) and AHRE (+) group (n=40). Real-time three-dimensional echocardiography (RT-3DE) technique was used to obtain the LA time-volume curve. The collected dynamic images were analyzed on the Echopac 204 workstation to obtain the parameters of LA. The four-dimensional automatic LA quantitative analysis (4D Auto LAQ) technology was used to analyze the LA strain parameters: LA reservoir longitudinal strain (LASr), LA conduit longitudinal strain (LAScd), LA contraction longitudinal strain (LASct), LA reservoir circumferential strain (LASr-c), LA conduit circumferential strain (LAScd-c), LA contraction circumferential strain (LASct-c). Correlation analysis was carried out using Binary logistic regression analysis. The area under the receiver operating characteristic (ROC) curve (AUC) was used to evaluate the diagnostic performance of LASct in AHRE. Results: Body surface area (BSA) [odds ratio (OR) =8.34, 95% confidence interval (CI): 1.32-72.30, P=0.037], LASct (OR =1.20, 95% CI: 1.05-1.39, P=0.013) and LA end-systolic volume (LAESV) (OR =1.02, 95% CI: 1.00-1.04, P=0.023) were the influencing factors of AHRE. Only LASct (OR =1.18, 95% CI: 1.01-1.38, P=0.041) was found to be an independent influencing factor of AHRE. This result remained significant after adjusting for age, sex, hypertension, diabetes, and stroke history. The ROC curve showed that the cut-off for predicting AHRE was LASct =-4.125% with sensitivity of 37.5% and specificity of 87.7%. Conclusions: This cross-sectional study found that decreased LASct (absolute value) is an independent risk factor for the AHRE and has diagnostic efficacy in certain degree for the occurrence of AHRE.

Advances in signal amplification strategies applied in pathogenic bacteria apta-sensing analysis-A review.

Pathogenic bacteria are primarily kinds of food hazards that provoke serious harm to human health via contaminated or spoiled food. Given that pathogenic bacteria continue to reproduce and expand once they contaminate food, pathogenic bacteria of high concentration triggers more serious losses and detriments. Hence, it is essential to detect low-dose pollution at an early stage with high sensitivity. Aptamers, also known as "chemical antibodies", are oligonucleotide sequences that have attracted much attention owing to their merits of non-toxicity, small size, variable structure as well as easy modification of functional group. Aptamer-based bioanalysis has occupied a critical position in the field of rapid detection of pathogenic bacteria. This is attributed to the unique advantage of using aptamers as recognition elements in signal amplification strategies. The signal amplification strategy is an effective means to improve the detection sensitivity. Some diverse signal amplification strategies emphasize the synthesis and assembly of nanomaterials with signal amplification capabilities, while others introduce various nucleic acid amplification techniques into the detection system. This review focuses on a variety of signal amplification strategies employed in aptamer-based detection approaches to pathogenic bacteria. Meanwhile, we provided a detailed introduction to the design principles and characteristics of signal amplification strategies, as well as the improvement of sensor sensitivity. Ultimately, the existing issues and development trends of applying signal amplification strategies in apta-sensing analysis of pathogenic bacteria are critically proposed and prospected. Overall, this review discusses from a new perspective and is expected to contribute to the further development of this field.

Empagliflozin alleviates atherosclerotic calcification by inhibiting osteogenic differentiation of vascular smooth muscle cells.

SGLT-2 inhibitors, such as empagliflozin, have been shown to reduce the occurrence of cardiovascular events and delay the progression of atherosclerosis. However, its role in atherosclerotic calcification remains unclear. In this research, ApoE-/- mice were fed with western diet and empagliflozin was added to the drinking water for 24 weeks. Empagliflozin treatment significantly alleviated arterial calcification assessed by alizarin red and von kossa staining in aortic roots and reduced the lipid levels, while had little effect on body weight and blood glucose levels in ApoE-/- mice. In vitro studies, empagliflozin significantly inhibits calcification of primary vascular smooth muscle cells (VSMCs) and aortic rings induced by osteogenic media (OM) or inorganic phosphorus (Pi). RNA sequencing of VSMCs cultured in OM with or without empagliflozin showed that empagliflozin negatively regulated the osteogenic differentiation of VSMCs. And further studies confirmed that empagliflozin significantly inhibited osteogenic differentiation of VSMCs via qRT-PCR. Our study demonstrates that empagliflozin alleviates atherosclerotic calcification by inhibiting osteogenic differentiation of VSMCs, which addressed a critical need for the discovery of a drug-based therapeutic approach in the treatment of atherosclerotic calcification.

How the trabeculae protrude within the left atrial appendage is the key factor affecting thrombosis in patients with atrial fibrillation.

The left atrial appendage (LAA) is a major site of thrombosis in patients with non-valvular atrial fibrillation. The myocardial trabeculae within the LAA have a peculiar tendency to protrude but its relationship to thrombosis remains unknown. This study aimed to investigate the relationship between the condition of trabeculae protrusion and LAA thrombosis. This retrospective study consecutively selected patients diagnosed with non-valvular atrial fibrillation and prepared for radiofrequency ablation from January 2011 to May 2020. Patients were divided into the thrombus group (n = 43), the sludge group (n = 35), and the normal group (n = 407) according to whether the thrombus or sludge was present. The trabeculae protruding angle (TPA), which was measured by the CT scans, was used to quantify the trabeculae protrusion condition. Patients' clinical data, TPA, LAA emptying velocity, and other factors were collected and compared among the three groups. A total of 485 patients were enrolled. The range of TPA was between 0 and 158 degrees, with an average of 89.3 ± 35.6 degrees. The TPA was significantly greater in the thrombus (109.3 ± 14.8 degrees) and sludge groups (110.8 ± 12.8 degrees) than in the normal group (85.3 ± 37.1). The incidence of LAA thrombus and sludge increased with increasing TPA. Multivariate regression analysis showed that the TPA was an independent risk factor for LAA thrombus (OR = 1.046, 95%CI: 1.020-1.073, p < 0.001) and sludge (OR = 1.035, 95%CI: 1.017-1.053, p < 0.001). Further analysis revealed that the TPA was negatively correlated with LAA emptying velocity but its effect on promoting thrombosis was not only mediated by slowing down the flow velocity. The TPA can well reflect the condition of trabeculae protrusion. This study revealed that the TPA was an independent risk factor for LAA thrombus or sludge, providing a potential indicator for future thrombosis risk assessment.

Left atrial enlargement and high uric acid level are risk factors for left atrial thrombus or dense spontaneous echo contrast in atrial fibrillation patients with low to moderate embolic risk assessed by CHA2DS2-VASC score.

Aims: To investigate the correlation and predictive value of left atrial diameter and blood uric acid levels with the occurrence of left atrial thrombus or dense spontaneous echo contrast in atrial fibrillation patients with low to moderate CHA2DS2-VASc scores. Methods and results: A total of 849 inpatients diagnosed with atrial fibrillation who had low to moderate CHA2DS2-VASc scores and complete transesophageal echocardiography were included in this study. Among them, 66 patients had left atrial thrombus or dense spontaneous echo contrast. When different models were used to correct other known risk factors, acid levels and abnormal left atrial diameter were identified as additional risk factors for left atrial thrombus or dense spontaneous echo contrast. The incidence of left atrial thrombus or dense spontaneous echo contrast was higher in patients with abnormal serum uric acid levels than in the control group (12.4% vs. 5.6%, p < 0.05), and this difference persisted after correcting the baseline data with propensity score matching (10.6% vs. 4.1%, p < 0.05). Abnormal left atrial diameter was another risk factor suggested by regression analysis, with an increased incidence of left atrial thrombus or dense spontaneous echo contrast in the abnormal left atrial diameter group compared to the control group, both before (18.0% vs. 3.5%, p < 0.05) and after (15.5% vs. 5.2%, p < 0.05) propensity score matching. The best predictive value was obtained by adding both abnormal serum uric acid levels and abnormal left atrial diameter. Conclusion: Left atrial enlargement and high uric acid levels increase the risk of left atrial thrombus or dense spontaneous echo contrast in atrial fibrillation patients with low to moderate CHA2DS2-VASc scores.

Amino acids downregulate SIRT4 to detoxify ammonia through the urea cycle.

Ammonia production via glutamate dehydrogenase is inhibited by SIRT4, a sirtuin that displays both amidase and non-amidase activities. The processes underlying the regulation of ammonia removal by amino acids remain unclear. Here, we report that SIRT4 acts as a decarbamylase that responds to amino acid sufficiency and regulates ammonia removal. Amino acids promote lysine 307 carbamylation (OTCCP-K307) of ornithine transcarbamylase (OTC), which activates OTC and the urea cycle. Proteomic and interactome screening identified OTC as a substrate of SIRT4. SIRT4 decarbamylates OTCCP-K307 and inactivates OTC in an NAD+-dependent manner. SIRT4 expression was transcriptionally upregulated by the amino acid insufficiency-activated GCN2-eIF2α-ATF4 axis. SIRT4 knockout in cultured cells caused higher OTCCP-K307 levels, activated OTC, elevated urea cycle intermediates and urea production via amino acid catabolism. Sirt4 ablation decreased male mouse blood ammonia levels and ameliorated CCl4-induced hepatic encephalopathy phenotypes. We reveal that SIRT4 safeguards cellular ammonia toxicity during amino acid catabolism.

Radiofrequency catheter ablation for improving myocardial work in patients with ventricular pre-excitation.

Background: Previous studies have not consistently found significant improvements in left ventricular ejection fraction or global longitudinal strain (GLS) after radiofrequency catheter ablation (RFCA) in patients with ventricular pre-excitation. The aim of this study was thus to explore the effects of RFCA on left ventricular function in patients with ventricular pre-excitation using a new noninvasive echocardiographic method of myocardial work. Methods: A total of 34 patients with ventricular pre-excitation who underwent RFCA and 18 healthy controls were prospectively included in this study. Before and after participants underwent RFCA, electrocardiographic and echocardiographic data of the patients were collected at resting and pacing heart rates (HRs) of 100 beats per minute (bpm) and 120 bpm (controlled by high right atrial pacing during the procedure). Clinical data of the healthy controls at resting HR were also collected. A self-controlled paired sample t test was used to compare the differences before and after participants underwent RFCA. Results: After participants underwent RFCA, the global wasted work (GWW) of the included patients decreased (resting HR: 165.3±68.8 vs. 92.6±42.5 mmHg%, P<0.001; HR of 100 bpm: 276.3±121.2 vs. 187.9±96.0 mmHg%, P<0.001; HR of 120 bpm: 323.9±126.7 vs. 181.0%±74.3 mmHg%. P<0.001), while the global work efficiency (GWE) increased (resting HR: 91.5%±3.8% vs. 94.9%±1.6%; P<0.001; HR of 100 bpm: 87.0%±5.2% vs. 91.0%±3.3%, P<0.001; HR of 120 bpm: 85.0%±5.1% vs. 90.3%±3.7%, P<0.001). Conclusions: In patients with ventricular pre-excitation, impaired GWW and GWE can be improved with RFCA. In clinical practice, noninvasive myocardial work assessment can be used in patients with ventricular pre-excitation.

Clinical characteristics of anti-AChR-MuSK-LRP4 antibody-negative myasthenia gravis in China.

INTRODUCTION/AIMS: Descriptions of the clinical characteristics of anti-AChR-MuSK-LRP4 antibody-negative myasthenia gravis (triple-negative myasthenia gravis, TNMG) are lacking in the current literature. Therefore, we investigated the clinical characteristics of TNMG in Chinese patients. METHODS: We retrospectively analyzed 925 patients with MG registered in the Department of Neuroimmunology, Henan Institute of Medical and Pharmaceutical Sciences from January 2015 to March 2021. RESULTS: One hundred six patients diagnosed with TNMG were included in the study. The average age of onset was 32.4 y, with a male-to-female ratio of 1:1. The age of onset showed a bimodal distribution: 0-9 y and 40-49 y. Adult patients were more likely to have weakness of limb and bulbar muscles (p < .05). Thymic hyperplasia was found in 20.2% of the patients. Younger patients were more likely to relapse. The rate of adult early-onset myasthenia gravis reaching complete stable remission and pharmacological remission was 47.6%, and the prognosis was better than that in juvenile-onset myasthenia gravis (p = .019). Older age of onset was the only risk factor for the development of generalized TNMG from ocular TNMG (R = 1.046, p = .002, 95% confidence interval 1.017-1.077). DISCUSSION: This study showed that the clinical characteristics of patients with TNMG varied among the different age groups. Significant findings included a bimodal distribution of onset age, coexisting thymic hyperplasia, and a generally favorable prognosis.

Sorting nexin 17 increases low-density lipoprotein receptor-related protein 4 membrane expression: A novel mechanism of acetylcholine receptor aggregation in myasthenia gravis.

Myasthenia gravis (MG) is characterized by autoimmune damage to the postsynaptic membrane of the neuromuscular junction (NMJ) with impaired postsynaptic acetylcholine receptor (AChR) aggregation. Low-density lipoprotein receptor-related protein 4 (LRP4) plays an important role in AChR aggregation at endplate membranes via the Agrin-LRP4-muscle-specific receptor tyrosine kinase (MuSK) cascade. Sorting nexin 17 (SNX17) regulates the degradation and recycling of various internalized membrane proteins. However, whether SNX17 regulates LRP4 remains unclear. Therefore, we examined the regulatory effects of SNX17 on LRP4 and its influence on AChR aggregation in MG. We selected C2C12 myotubes and induced LRP4 internalization via stimulation with anti-LRP4 antibody and confirmed intracellular interaction between SNX17 and LRP4. SNX17 knockdown and overexpression confirmed that SNX17 promoted MuSK phosphorylation and AChR aggregation by increasing cell surface LRP4 expression. By establishing experimental autoimmune MG (EAMG) mouse models, we identified that SNX17 upregulation improved fragmentation of the AChR structure at the NMJ and alleviated leg weakness in EAMG mice. Thus, these results reveal that SNX17 may be a novel target for future MG therapy.

Association of latent class analysis-derived subphenotypes of acute kidney injury with mortality in critically ill patients with cardiovascular disease: a retrospective cohort study.

BACKGROUND: To explore the potential heterogeneity of acute kidney injury (AKI) and evaluate the prognostic differences among AKI subphenotypes in critically ill patients with cardiovascular diseases. METHODS: Data were extracted from the Medical Information Mart for Intensive Care (MIMIC)-III database. Latent class analysis (LCA) was used to explore the potential subphenotypes of AKI in critically ill patients with cardiovascular diseases. The number of classes was identified by the Bayesian information criterion and entropy. The differences in prognostic ability among the AKI subphenotypes were evaluated by logistic regression analysis. RESULT: A total of 7738 AKI patients were enrolled in this study. Using LCA, AKI patients were divided into 4 heterogeneous subphenotypes, which were obviously different from the Kidney Disease: Improving Global Outcomes (KDIGO) stages. Interestingly, class 3 classified by LCA was dominated by stage 2, while the mortality rate in class 3 was significantly different from that in class 1 (15.2% vs. 1.6%, p < 0.05). After further adjustment, the mortality rate in class 3 remained higher than that in class 1, with an odds ratio of 12.31 (95% confidence interval, 8.96-16.89). CONCLUSIONS: LCA was feasible for AKI classification in critically ill patients with cardiovascular disease, and 4 distinct subphenotypes of AKI patients with different prognoses were identified. Our results highlighted the potential heterogeneity of AKI patients, which is worthy of further investigation.

Methylene-bridge tryptophan fatty acylation regulates PI3K-AKT signaling and glucose uptake.

Protein fatty acylation regulates numerous cell signaling pathways. Polyunsaturated fatty acids (PUFAs) exert a plethora of physiological effects, including cell signaling regulation, with underlying mechanisms to be fully understood. Herein, we report that docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) regulate PI3K-AKT signaling by modifying PDK1 and AKT2. DHA-administered mice exhibit altered phosphorylation of proteins in signaling pathways. Methylene bridge-containing DHA/EPA acylate δ1 carbon of tryptophan 448/543 in PDK1 and tryptophan 414 in AKT2 via free radical pathway, recruit both the proteins to the cytoplasmic membrane, and activate PI3K signaling and glucose uptake in a tryptophan acylation-dependent but insulin-independent manner in cultured cells and in mice. DHA/EPA deplete cytosolic PDK1 and AKT2 and induce insulin resistance. Akt2 knockout in mice abrogates DHA/EPA-induced PI3K-AKT signaling. Our results identify PUFA's methylene bridge tryptophan acylation, a protein fatty acylation that regulates cell signaling and may underlie multifaceted effects of methylene-bridge-containing PUFAs.

Predicting Risk Factors of Acute Kidney Injury in the First 7 Days after Admission: Analysis of a Group of Critically Ill Patients.

Background: Acute kidney injury (AKI) is a common complication in critically ill patients. Some predictive models have been reported, but the conclusions are controversial. The aim of this study was the formation of nomograms to predict risk factors for AKI in critically ill patients within the first 7 days after admission to the intensive care unit (ICU). Methods: Data were extracted from the Medical Information Mart for Intensive Care- (MIMIC-) III database. The random forest method was used to fill in the missing values, and least absolute shrinkage and selection operator (Lasso) regression analysis was performed to screen for possible risk factors. Results: A total of 561 patients were enrolled. Complication with AKI is significantly associated with a longer length of stay (LOS). For all patients, the predictors contained in the prediction nomogram included hypertension, coronary artery disease (CAD), cardiopulmonary bypass (CPB), coronary artery bypass grafting (CABG), Simplified Acute Physiology Score II (SAPS II), central venous pressure (CVP) measured for the first time after admission, and maximum and minimum mean artery pressure (MAP). The model showed good discrimination (C - index = 0.818, 95% CI: 0.779-0.857). In the subgroup of patients with well-controlled blood glucose levels, the significant predictors included hypertension, CABG, CPB, SAPS II, and maximum and minimum MAP. Good discrimination was also present before (C - index = 0.785, 95% CI: 0.736-0.834) and after adjustment (adjusted C - index = 0.770). Conclusion: Hypertension, CAD, CPB, CABG, SAPS II, CVP measured for the first time after admission, and maximum and minimum MAP were independent risk factors for AKI in critically ill patients.

No correlation between acetylcholine receptor antibody concentration and individual clinical symptoms of myasthenia gravis: A systematic retrospective study involving 67 patients.

OBJECTIVE: To investigate the correlation between acetylcholine receptor antibodies (AChR-Ab) concentration levels and individualized clinical symptoms in patients with AChR myasthenia gravis (AChR-MG) in China. METHODS: ELISA was used to determine the concentration of AChR-Ab in patients with MG. The Myasthenia Gravis Foundation of America (MGFA) Clinical Classification, Quantitative Myasthenia Gravis (QMG) score, and MG-specific activities of daily living (MG-ADL) scoring systems were used to evaluate the clinical status of patients. Spearman correlation analysis was used to determine the correlation between the AChR-Ab concentration and clinical score. The changes in the antibody concentration and clinical score are shown in MGFA-antibody concentration-treatment plots. RESULTS: Autoantibody detection tests were performed in 67 patients, and their clinical scores were recorded. Forty-nine patients received immunosuppressive therapy, 17 patients received pyridostigmine only, and 1 patient under thymectomy without any medication. The AChR-Ab concentration correlated with the MGFA Classification in 5 (29.4%) patients in the pyridostigmine-only group and 15 (30.6%) patients in the immunosuppressive drug group. The changes in the MGFA Classification preceded the changes in the AChR-Ab concentration in 4 (23.5%) patients treated with pyridostigmine and 10 (20.4%) patients on immunosuppressive drugs. In patients on oral non-steroidal immunosuppressants, the AChR-Ab concentration changed by more than 50%, whereas the MGFA Classification did not increase. The AChR-Ab concentration decreased in 17/32 (53.1%) patients after thymectomy, and then increased, whereas the AChR-Ab concentration increased in 15/32 (46.9%) patients and the MGFA Classification decreased in 27/32 (81.8%) patients after thymectomy. The AChR-Ab concentration presented a slight correlation with the corresponding MGFA, QMG, and MG-ADL in patients with thymoma. DISCUSSION: In the Chinese AChR-MG population, the Changes in the AChR-Ab concentration in individuals with AChR-MG did not consistently correlate with the severity of clinical symptoms.

Heart rate fluctuation predicts mortality in critically ill patients in the intensive care unit: a retrospective cohort study.

BACKGROUND: To evaluate the association between heart rate (HR) fluctuation and mortality in critically ill patients in the intensive care unit (ICU). METHODS: A total of 27,814 patients were enrolled from the Medical Information Mart for Intensive Care database and were divided into 3 groups: low HR fluctuation [<25 beats per minute (bpm)], control (25-34 bpm), and high HR fluctuation (≥35 bpm), based on the initial 24-hour HR fluctuation (calculated as the maximum HR minus minimum HR). Multivariate Cox regression and restricted cubic spline models were used. RESULTS: Compared to the control group, higher risk of 28-day and 1-year mortality remained significant in an adjusted model, with hazard ratios of 1.210 [95% confidence interval (CI), 1.103-1.327] and 1.150 (95% CI, 1.078-1.227), respectively, in the high HR fluctuation group, as well as hazard ratios of 1.130 (95% CI, 1.035-1.232) and 1.087 (95% CI, 1.022-1.157), respectively, in the low HR fluctuation group. Restricted cubic splines showed a U-type curve, with the lowest risk of mortality at an HR fluctuation of 30 bpm. CONCLUSIONS: This retrospective cohort study revealed that both high and low HR fluctuation correlated with increased mortality in critically ill ICU patients, providing new insights for optimizing HR control strategies.

ß-elemene promotes the senescence of glioma cells through regulating YAP-CDK6 signaling.

Glioma is currently the most widespread and malignant primary intracranial tumor, which is characterized by high heterogeneity and high fatality rates. ß-elemene, which is a bioactive compound extracted from a Chinese herb, Curcuma wenyujin, has been reported to reduce resistance of chemotherapeutic drugs and induce apoptosis in tumor cells. However, the role and mechanisms of ß-elemene in glioma senescence remains unknown. In the present study, we found that a low concentration of ß-elemene (10 µg/mL) induced senescence in glioma cells, including reduction of cell proliferation, hypertrophic morphology, increase of senescence-associated ß-galactosidase (SA-ß-Gal) activity, upregulation of several senescence-associated genes such as p16, p53 and NF-κB, and downregulation of Lamin B1. However, a high concentration of ß-elemene induced apoptosis in glioma cells. Treatment with ß-elemene caused a marked down-regulation of Yes-associated protein (YAP) expression in glioma cells, which is a key transcriptional co-activator in multiple cancers. Moreover, cyclin dependent kinase 6 (CDK6), which is a known downstream target of YAP, was decreased in glioma cells that treated with ß-elemene. The overexpression of YAP and CDK6 significantly rescued ß-elemene-induced senescence in glioma cells. Finally, ß-elemene treatment also induced the senescence of glioma cells in glioma xenograft model through inactivation of YAP-CDK6 pathways, which might inhibit the glioma growth. Taken together, these results reveal a previously unknown role of ß-elemene in glioma cell senescence in vitro and in vivo that is associated with YAP-CDK6 signaling pathway, which will enhance our understanding of glioma cell senescence, and provide novel strategies for the treatment of gliomas.

Fast and effective recovery of Au(III) from aqueous solution by a N-containing polymer.

In this work, a N-containing polymer was successfully synthesized by one-step treatment with 3-amine-1,2,4-triazole ligands and Zn(II) using the thermal solvent method, and employed to recover Au(III) from water. The adsorption kinetics was comprehensively studied through kinetics models including pseudo-first-order model, pseudo-second-order model, moving boundary model and Weber-Morris model. It is found that the overall adsorption rate was determined by chemical adsorption, and the rate-limiting step of diffusion steps is film diffusion. Rising temperature can improve the adsorption rate significantly, making the adsorption equilibrium time be reduced from 6 h at 298 K to 2 h at 318 K. The adsorption isotherm can be described well by Sips model, indicating it is a heterogeneous adsorption. The material shows high adsorption capacity towards Au(III) up to 1073 mg/g. It shows strong affinity towards Au(III) in the mixture solutions containing Au(III), Cu(II), Zn(II), Co(II), Cd(II), Pb(II) and Ni(II) ions. The material can be easily and completely desorbed by thiourea solution and still maintains its adsorption performance only with a slight decrease after three cycles. Combined with studies on pH influence, adsorption kinetics, adsorption isotherm and XPS analysis, it can be concluded that the adsorption mechanism could be attributed to electrostatic interaction, the coordination of the Zn-OH and -C-N/-CN- with Au(III), and partial reduction of Au(III) to Au(I) by -NH group on the polymer. The N-containing polymer is an excellent candidate for Au(III) recovery efficiently and selectively from aqueous solution.

Inactivation of the AMPK-GATA3-ECHS1 Pathway Induces Fatty Acid Synthesis That Promotes Clear Cell Renal Cell Carcinoma Growth.

The tumorigenic role and underlying mechanisms of lipid accumulation, commonly observed in many cancers, remain insufficiently understood. In this study, we identified an AMP-activated protein kinase (AMPK)-GATA-binding protein 3 (GATA3)-enoyl-CoA hydratase short-chain 1 (ECHS1) pathway that induces lipid accumulation and promotes cell proliferation in clear cell renal cell carcinoma (ccRCC). Decreased expression of ECHS1, which is responsible for inactivation of fatty acid (FA) oxidation and activation of de novo FA synthesis, positively associated with ccRCC progression and predicted poor patient survival. Mechanistically, ECHS1 downregulation induced FA and branched-chain amino acid (BCAA) accumulation, which inhibited AMPK-promoted expression of GATA3, a transcriptional activator of ECHS1. BCAA accumulation induced activation of mTORC1 and de novo FA synthesis, and promoted cell proliferation. Furthermore, GATA3 expression phenocopied ECHS1 in predicting ccRCC progression and patient survival. The AMPK-GATA3-ECHS1 pathway may offer new therapeutic approaches and prognostic assessment for ccRCC in the clinic. SIGNIFICANCE: These findings uncover molecular mechanisms underlying lipid accumulation in ccRCC, suggesting the AMPK-GATA3-ECHS1 pathway as a potential therapeutic target and prognostic biomarker.