A D-π-A-type ratiometric fluorescent probe to detect polarity changes and inhibition effect during ferroptosis.

To thoroughly understand ferroptosis's biological functions in living cells, it is crucial to investigate the polarity variations that occur during this unique Fe(II)-facilitated oxidative type of cell death. In this work, we report the development of a ratiometric probe (Po-P) to visualize the polarity changes in living cells and the inhibition effect during ferroptosis. The polarity-responsive fluorophore utilized by Po-P has a D-π-A-type structure. Based on theoretical calculations, ICT was proposed as the basis for Po-P's polarity-responsive mechanism. According to cell imaging results, Po-P had a desirable capacity for monitoring polarity fluctuations and erastin-induced ferroptosis. Furthermore, inhibition imaging revealed that dihydrolipoic acid (DHLA) could potentially prevent polarity changes that occur during erastin-induced ferroptosis, just as vitamin E (VE). We anticipate that the probe Po-P could be a valuable tool to quickly monitor polarity fluctuations and inhibition effects during ferroptosis and create new medications for treating disorders related to ferroptosis.

Development of bishydrazide-based fluorescent probes for the imaging of cellular peroxynitrite (ONOO-) during ferroptosis.

Peroxynitrite (ONOO-) is a critical ROS in living systems, and could induce lipid peroxidation which is the driver of ferroptotic cell death. Therefore, precise and rapid detection of cellular ONOO- is critical for the deep study of the biological functions of ONOO- during ferroptosis. Herein, we developed fluorescent probes (Rh-1, Rh-2 and Rh-3) for the rapid detection of intracellular ONOO- during ferroptosis. These probes used bishydrazide groups as the reactive sites for ONOO-. The response of these probes to ONOO- resulted in the production of the emissive xanthene fluorophore, providing a marked enhancement in the fluorescence intensity at 561 nm. The probe Rh-3 exhibited prominent selectivity and sensitivity towards ONOO-. Bioimaging experiments suggested that Rh-3 could be applied to image exogenous and endogenous ONOO- in living cells. By fluorescence imaging, it was demonstrated that erastin-induced ferroptosis caused increased levels of the endogenous ONOO-, and ferrostatin-1 (Fer-1) and vitamin E (VE) could markedly inhibit the excessive production of ONOO- during ferroptosis in living cells.

Chiral Carbon Dots and Chiral Carbon Dots with Circularly Polarized Luminescence: Synthesis, Mechanistic Investigation and Applications.

Chiral carbon dots (CCDs) can be widely used in various fields such as chiral recognition, chiral catalysis and biomedicine because of their unique optical properties, low toxicity and good biocompatibility. In addition, CCDs with circularly polarized luminescence (CPL) can be synthesized, thus broadening the prospects of CCDs applications. Since the research on CCDs is still in its infancy, this paper reviews the chiral origin, formation mechanism, chiral evolution, synthesis and emerging applications of CCDs, with a special focus on CCDs with CPL activity. It is hoped that it will provide some reference to solve the current problems faced by CCDs. Finally, the opportunities and challenges of the current research on CCDs are described, and their future development trends have also been prospected.

A D-π-A-π-D type structure-based fluorescent probe for revealing the fluctuations of the ER polarity during ferroptosis.

Ferroptosis is a novel Fe(II)-mediated oxidative cell death form, and is closely related with endoplasmic reticulum (ER). Exploring the fluctuation of ER polarity during ferroptosis is highly important for the in-depth study of the biological roles of ER in ferroptosis. Herein, we present a ratiometric probe (BNS) for revealing the changes of the ER polarity in the living cells experiencing ferroptosis. BNS employed a D-π-A-π-D type structure as the polarity-sensitive fluorophore, and selected p-toluenesulfonamide as the ER-targeting unit. Theoretical calculations suggested that the response mechanism of BNS to polarity was based on ICT, and two ICT processes appeared when BNS was at excited state. Cell imaging results demonstrated that BNS possessed desirable ER-targeting capability, and erastin-induced ferroptosis could increase the ER polarity of the living cells. Moreover, similarly to vitamin E (VE) and deferoxamine (DFO), dihydrolipoic acid (DHLA) could inhibit the changes of the ER polarity during erastin-induced ferroptosis. We expect that the probe could provide a convenient method to rapidly monitor ferroptosis and design novel drugs for the treatment of ferroptosis-relevant diseases.

Fluorescence Imaging of Intracellular Glutathione Levels in the Endoplasmic Reticulum to Reveal the Inhibition Effect of Rutin on Ferroptosis.

Ferroptosis is an emerging form of nonapoptotic cell death, and the search for novel ferroptosis inhibitors is of great importance to explore unique cytoprotective strategies against ferroptosis-relevant diseases. In this work, we present an endoplasmic reticulum-targeting fluorescent probe (ER-G) for the imaging of intracellular glutathione (GSH) levels and revealed the inhibition effect of rutin on ferroptosis. Structurally, ER-G utilized a cyclohexyl sulfonylurea as the endoplasmic reticulum-targeting unit, and single-crystal X-ray diffraction analysis confirmed that ER-G possessed a N-oxide pyridine sulfinyl group instead of sulfone. After the response of ER-G to GSH, the fluorescence intensity at 523 nm displayed a significant increase by 3900-fold. ER-G showed extreme sensitivity and selectivity to GSH. The fluorescence imaging results demonstrated that ER-G exhibited excellent endoplasmic reticulum-targeting properties and could be applied to monitor GSH levels in the endoplasmic reticulum during the erastin-induced ferroptosis process. By the fluorescence imaging of GSH levels in the endoplasmic reticulum, it was demonstrated that rutin could efficiently block the depletion of GSH during erastin-induced ferroptosis and potentially act as a novel ferroptosis inhibitor. Moreover, unlike traditional ferroptosis inhibitors, it was speculated that the inhibition mechanism of rutin to ferroptosis was the integration of the chelate effect on Fe(II) ions and antioxidant effect. We expect that fluorescence imaging of GSH levels in the endoplasmic reticulum could provide a convenient and feasible method to evaluate the inhibition effect of small molecules on ferroptosis.

Simulation Research on the Methods of Multi-Gene Region Association Analysis Based on a Functional Linear Model.

Genome-wide association analysis is an important approach to identify genetic variants associated with complex traits. Complex traits are not only affected by single gene loci, but also by the interaction of multiple gene loci. Studies of association between gene regions and quantitative traits are of great significance in revealing the genetic mechanism of biological development. There have been a lot of studies on single-gene region association analysis, but the application of functional linear models in multi-gene region association analysis is still less. In this paper, a functional multi-gene region association analysis test method is proposed based on the functional linear model. From the three directions of common multi-gene region method, multi-gene region weighted method and multi-gene region loci weighted method, that test method is studied combined with computer simulation. The following conclusions are obtained through computer simulation: (a) The functional multi-gene region association analysis test method has higher power than the functional single gene region association analysis test method; (b) The functional multi-gene region weighted method performs better than the common functional multi-gene region method; (c) the functional multi-gene region loci weighted method is the best method for association analysis on three directions of the common multi-gene region method; (d) the performance of the Step method and Multi-gene region loci weighted Step for multi-gene regions is the best in general. Functional multi-gene region association analysis test method can theoretically provide a feasible method for the study of complex traits affected by multiple genes.

Gene Region Association Analysis of Longitudinal Quantitative Traits Based on a Function-On-Function Regression Model.

In the process of growth and development in life, gene expressions that control quantitative traits will turn on or off with time. Studies of longitudinal traits are of great significance in revealing the genetic mechanism of biological development. With the development of ultra-high-density sequencing technology, the associated analysis has tremendous challenges to statistical methods. In this paper, a longitudinal functional data association test (LFDAT) method is proposed based on the function-on-function regression model. LFDAT can simultaneously treat phenotypic traits and marker information as continuum variables and analyze the association of longitudinal quantitative traits and gene regions. Simulation studies showed that: 1) LFDAT performs well for both linkage equilibrium simulation and linkage disequilibrium simulation, 2) LFDAT has better performance for gene regions (include common variants, low-frequency variants, rare variants and mixture), and 3) LFDAT can accurately identify gene switching in the growth and development stage. The longitudinal data of the Oryza sativa projected shoot area is analyzed by LFDAT. It showed that there is the advantage of quick calculations. Further, an association analysis was conducted between longitudinal traits and gene regions by integrating the micro effects of multiple related variants and using the information of the entire gene region. LFDAT provides a feasible method for studying the formation and expression of longitudinal traits.

Endovascular treatment for acute ischemic stroke in patients with versus without atrial fibrillation: a matched-control study.

BACKGROUND AND OBJECTIVE: The effect of atrial fibrillation (AF) on outcomes of endovascular treatment (EVT) for acute ischemic stroke (AIS) is controversial. This study aimed to investigate the association of AF with outcomes after EVT in AIS patients. METHODS: Subjects were selected from ANGEL-ACT registry (Endovascular Treatment Key Technique and Emergency Work Flow Improvement of Acute Ischemic Stroke) - a prospective consecutive cohort of AIS patients undergoing EVT at 111 hospitals in China between November 2017 and March 2019, and then grouped according to having a history of AF or not. After 1:1 propensity score matching, the outcome measures including the 90-day modified Rankin Scale (mRS) score, successful recanalization after final attempt, symptomatic intracranial hemorrhage (ICH) within 24 h, and death within 90 days were compared. RESULTS: A total of 1755 patients, 550 with AF and 1205 without AF, were included. Among 407 pairs of patients identified after matching, no significant differences were found in the mRS score (median: 3 vs. 3 points; P = 0.29), successful recanalization (87.2 vs. 85.3%; P = 0.42), symptomatic ICH (9. 4 vs. 9.1%; P = 0.86) and death (16.3 vs. 18.4%; P = 0.44) between patients with and without AF. CONCLUSION: The findings of this matched-control study show comparable outcomes of EVT in Chinese AIS patients with and without AF, which do not support withholding EVT in patients with both AIS and AF. TRIAL REGISTRATION: NCT03370939 First registration date: 28/09/2017 First posted date: 13/12/2017.

The significance of eosinophils in predicting the severity of acute ischemic stroke.

BACKGROUND: Previous studies have shown that tumor-associated tissue eosinophilia have a role in various types of solid tumors. However, the relationship between eosinophil and acute ischemic stroke (AIS) is unclear. We aimed to investigate the diagnostic significance of eosinophil in AIS patients. METHODS: This study included 300 AIS patients without hypereosinophilic syndrome (HES). The hematologic indices were collected from each patient, including white blood count, eosinophil count, eosinophil percentage, neutrophil count, red blood count, and platelet. The severity of AIS was estimated by national institute of health stroke scale (NIHSS). Logistic regression analyses were performed to confirm the biomarkers for NIHSS and in-hospital non-death among the cases. Moreover, receiver-operating characteristics (ROC) analyses were used to investigate the clinical performances of eosinophils and NIHSS in prediction of non-death. RESULTS: The admission NIHSS (P<0.001) and BMI (P<0.001) were predictors to the non-death of the patients. There was a significant correlation between eosinophil counts or eosinophil percentage and NIHSS score (r= -0.451, P < 0.001; r= -0.617, P<0.001, Spearson Correlation). ROC analysis showed that eosinophil counts and eosinophil percentage could predict non-death of the patients in-hospital, with the areas under the curves (AUC) of 0.791 and 0.867, respectively. CONCLUSIONS: Our study revealed a relationship between eosinophil and NIHSS score in the patients with AIS. Eosinophils might have certain value for predicting the severity of AIS.

Ultrasound-Guided Second Trimester Fetal Electroencephalography in Two Pregnant Volunteers: A Technical Note.

BACKGROUND AND PURPOSE: Data from electroencephalography (EEG) in preterm infants and neonates suggest that electroencephalographic abnormalities are likely present during antepartum period or fetal stage. We describe our initial effort to record fetal EEG with emphasis on technical aspects since such technique has not been developed as a viable and reproducible method. METHODS: The fetal heads were located in two pregnant volunteers (29 years old and 26 years old) with 28 weeks of gestation by ultrasound imaging. Four surface electrodes were placed on maternal abdominal surface approximately 5 cm anterior to the lateral aspect of fetal head as confirmed by acoustic shadowing of the electrodes on ultrasound. A second set of recordings were performed in first volunteer with four electrodes placed on the maternal abdominal surface in front of the uterus distant to fetal head. RESULTS: The analysis in the first volunteer demonstrated that the activity consisted of mixture of theta (4-7 Hz) and delta (1-4 Hz) waves which formed approximately 70% and 30% of the background rhythm. The analysis in the second volunteer demonstrated that the activity consisted of mixture of theta and delta, which formed approximately 30% and 70% of the background rhythm. There was superimposed beta (13-30 Hz) and infrequently gamma (30-100 Hz) activity. Maternal electrocardiographic QRS complex and respiratory artifacts were seen in some leads. During second recording, the electrodes distant to fetal head recorded predominantly delta with lesser proportion of theta waves. CONCLUSIONS: We report our initial experience in acquisition of fetal EEG. The findings reported here will help to guide further research into developing methodologies for the performance of fetal EEG.

Relationship of coronary collateral circulation with eosinophils in patients with unstable angina pectoris.

BACKGROUND: Eosinophils (EOS) have been associated with prognosis of patients with coronary artery disease, and those who showed plenitudinous coronary collateral circulation (CCC) often have good clinical consequences. However, the relationship between EOS and CCC was seldom reported. OBJECTIVE: To investigate the relationship between EOS and CCC development in patients with unstable angina pectoris (UAP). METHODS: The study population consisted of 502 consecutive patients with UAP who underwent coronary angiography and coronary stenosis ≥80%. CCC was graded according to the Rentrop grading system of 0-3. Rentrop grades of 0 and 1 indicated low-grade CCC group, whereas grades 2 and 3 indicated high-grade CCC group. RESULTS: The EOS was significantly higher in the high-grade CCC group compared with the low-grade CCC group. In multiple logistic regression analysis, EOS (odds ratio: 1.969; 95% confidence interval [CI]: 1.210-3.3205; P=0.006) and neutrophil count (odds ratio: 0.757; 95% CI: 0.584-0.981; P=0.035) were predictors of high-grade CCC development. EOS of >0.12×10(9)/L could independently predict high-grade CCC with 72.5% sensitivity and 58.4% specificity (area under the curve: 0.681; 95% CI: 0.632-0.729). CONCLUSION: EOS were associated with high-grade CCC in patients with UAP with coronary stenosis ≥80%. Increased EOS count may play an important role in the development of CCC in patients with UAP.

Helicobacter pylori infection in Chinese patients with atrial fibrillation.

OBJECTIVE: To explore the relationship between Helicobacter pylori (Hp) infection and atrial fibrillation (AF) in Chinese patients. METHODS: A total of 285 hospitalized patients with AF and 300 patients from Health Screening Center who matched age and sex with AF group were enrolled. AF patients were divided into two groups: the short-standing AF category (less than a year) and the long-standing AF category (more than a year). All patients had laboratory testing of (13)C urea breath test, high-sensitive C-reactive protein (hs-CRP) and left atrial diameter (LAD). We analyzed the difference of these factors in all groups and explored the correlation between Hp infection and AF using logistic regression analysis. RESULTS: Both AF groups had more hypertension, diabetes, and Hp infection than the control group. The Hp value and the hs-CRP level in patients with long-standing AF were higher than those in the short-standing AF and the control groups (for Hp value: P<0.001 for both and for hs-CRP level: P=0.003, 0.002, respectively). The LAD of patients in the long-standing AF group was significantly larger than those in the short-standing AF group and control group (P=0.001 and P<0.001, respectively). The values of Hp, hs-CRP, and LAD in the long-standing AF category were significantly higher than those in the short-standing AF category (all P<0.05). After controlling the potential confounders, Hp value ≥4‰, hs-CRP >5 mg/L, and LAD >36 mm were significantly related to long-standing AF. CONCLUSION: The values of Hp in patients with long-standing AF were significantly higher than those in short-standing AF and control groups. Hp δ value ≥4‰ is an independent predictor for long-standing AF.