Reteplase versus Alteplase for Acute Ischemic Stroke.

BACKGROUND: Alteplase is the standard agent used in early reperfusion therapy, but alternative thrombolytic agents are needed. The efficacy and safety of reteplase as compared with alteplase in patients with acute ischemic stroke are unclear. METHODS: We randomly assigned patients with ischemic stroke within 4.5 hours after symptom onset in a 1:1 ratio to receive intravenous reteplase (a bolus of 18 mg followed 30 minutes later by a second bolus of 18 mg) or intravenous alteplase (0.9 mg per kilogram of body weight; maximum dose, 90 mg). The primary efficacy outcome was an excellent functional outcome, defined as a score of 0 or 1 on the modified Rankin scale (range, 0 [no neurologic deficit, no symptoms, or completely recovered] to 6 [death]) at 90 days. The primary safety outcome was symptomatic intracranial hemorrhage within 36 hours after symptom onset. RESULTS: A total of 707 patients were assigned to receive reteplase, and 705 were assigned to receive alteplase. An excellent functional outcome occurred in 79.5% of the patients in the reteplase group and in 70.4% of those in the alteplase group (risk ratio, 1.13; 95% confidence interval [CI], 1.05 to 1.21; P<0.001 for noninferiority and P = 0.002 for superiority). Symptomatic intracranial hemorrhage within 36 hours after disease onset was observed in 17 of 700 patients (2.4%) in the reteplase group and in 14 of 699 (2.0%) of those in the alteplase group (risk ratio, 1.21; 95% CI, 0.54 to 2.75). The incidence of any intracranial hemorrhage at 90 days was higher with reteplase than with alteplase (7.7% vs. 4.9%; risk ratio, 1.59; 95% CI, 1.00 to 2.51), as was the incidence of adverse events (91.6% vs. 82.4%; risk ratio, 1.11; 95% CI, 1.03 to 1.20). CONCLUSIONS: Among patients with ischemic stroke within 4.5 hours after symptom onset, reteplase was more likely to result in an excellent functional outcome than alteplase. (Funded by China Resources Angde Biotech Pharma and others; RAISE ClinicalTrials.gov number, NCT05295173.).

Safety and Efficacy of Reteplase Versus Alteplase for Acute Ischemic Stroke: A Phase 2 Randomized Controlled Trial.

BACKGROUND: Reteplase is a more affordable new-generation thrombolytic with a prolonged half-life. We aimed to determine the safety dose range of reteplase for patients with acute ischemic stroke within 4.5 hours of onset. METHODS: This is a multicenter, prospective, randomized controlled, open-label, blinded-end point phase 2 clinical trial. Patients with acute ischemic stroke aged between 18 and 80 years who were eligible for standard intravenous thrombolysis were enrolled from 17 centers in China and randomly assigned (1:1:1) to receive intravenous reteplase 12+12 mg, intravenous reteplase 18+18 mg, or intravenous alteplase 0.9 mg/kg. The primary safety outcome was symptomatic intracranial hemorrhage (SITS definition) within 36 hours. The primary efficacy outcome was the proportion of patients with the National Institutes of Health Stroke Scale score of no more than 1 or a decrease of at least 4 points from the baseline at 14 days after thrombolysis. RESULTS: Between August 2019 and May 2021, 180 patients were randomly assigned to reteplase 12+12 mg (n=61), reteplase 18+18 mg (n=67), or alteplase (n=52). Four patients did not receive the study agent. Symptomatic intracranial hemorrhage occurred in 3 of 60 (5.0%) in the reteplase 12+12 mg group, 1 of 66 (1.5%) in the reteplase 18+18 mg group, and 1 of 50 (2.0%) in the alteplase group (P=0.53). The primary efficacy outcome in the modified intention-to-treat population occurred in 45 of 60 (75.0%) in the reteplase 12+12 mg group (odds ratio, 0.85 [95% CI, 0.35-2.06]), 48 of 66 (72.7%) in the reteplase 18+18 mg group (odds ratio, 0.75 [95% CI, 0.32-1.78]), and 39 of 50 (78.0%) in alteplase group. CONCLUSIONS: Reteplase was well tolerated in patients with acute ischemic stroke within 4.5 hours of onset in China with a similar efficacy profile to alteplase. The efficacy and appropriate dosage of reteplase for patients with acute ischemic stroke need prospective validation. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04028518.

Tenecteplase versus alteplase in acute ischaemic cerebrovascular events (TRACE-2): a phase 3, multicentre, open-label, randomised controlled, non-inferiority trial.

BACKGROUND: There is increasing interest in replacing alteplase with tenecteplase as the preferred thrombolytic treatment for patients with acute ischaemic stroke. We aimed to establish the non-inferiority of tenecteplase to alteplase for these patients. METHODS: In this multicentre, prospective, open-label, blinded-endpoint, randomised controlled, non-inferiority trial, adults with an acute ischaemic stroke who were eligible for standard intravenous thrombolysis but ineligible for endovascular thrombectomy were enrolled from 53 centres in China and randomly assigned (1:1) to receive intravenous tenecteplase (0·25 mg/kg, maximum dose of 25 mg) or intravenous alteplase (0·9 mg/kg, maximum dose of 90 mg). Participants had to be able to receive treatment within 4·5 h of stroke, have a modified Rankin Scale (mRS) score of no more than 1 before enrolment, and have a National Institutes of Health Stroke Scale score of 5-25. Patients and treating clinicians were not masked to group assignment; clinicians evaluating outcomes were masked to treatment type. The primary efficacy outcome was the proportion of participants who had a mRS score of 0-1 at 90 days, assessed in the modified intention-to-treat population (all randomly assigned participants who received the allocated thrombolytic), with a non-inferiority margin of 0·937 for the risk ratio (RR). The primary safety outcome was symptomatic intracranial haemorrhage within 36 h, assessed in all participants who received study drug and had a safety assessment available. The trial is registered with ClinicalTrials.gov, NCT04797013, and has been completed. FINDINGS: Between June 12, 2021, and May 29, 2022, 1430 participants were enrolled and randomly assigned to tenecteplase (n=716) or alteplase (n=714). Six patients assigned to tenecteplase and seven to alteplase did not receive study product, and five participants in the tenecteplase group and 11 in the alteplase group were lost to follow-up at 90 days. The primary outcome in the modified intention-to-treat population occurred in 439 (62%) of 705 in the tenecteplase group versus 405 (58%) of 696 in the alteplase group (RR 1·07, 95% CI 0·98-1·16). The lower limit of the RR's 95% CI was greater than the non-inferiority margin. Symptomatic intracranial haemorrhage within 36 h was observed in 15 (2%) of 711 in the tenecteplase group and 13 (2%) of 706 in the alteplase group (RR 1·18, 95% CI 0·56-2·50). Mortality within 90 days occurred in 46 (7%) individuals in the tenecteplase group versus 35 (5%) in the alteplase group (RR 1·31, 95% CI 0·86-2·01). INTERPRETATION: Tenecteplase was non-inferior to alteplase in people with ischaemic stroke who were eligible for standard intravenous thrombolytic but ineligible for or refused endovascular thrombectomy. FUNDING: National Science and Technology Major Project, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, National Natural Science Foundation of China, and China Shijiazhuang Pharmaceutical Company Recomgen Pharmaceutical (Guangzhou).

MolSHAP: Interpreting Quantitative Structure-Activity Relationships Using Shapley Values of R-Groups.

Optimizing the activities and properties of lead compounds is an essential step in the drug discovery process. Despite recent advances in machine learning-aided drug discovery, most of the existing methods focus on making predictions for the desired objectives directly while ignoring the explanations for predictions. Although several techniques can provide interpretations for machine learning-based methods such as feature attribution, there are still gaps between these interpretations and the principles commonly adopted by medicinal chemists when designing and optimizing molecules. Here, we propose an interpretation framework, named MolSHAP, for quantitative structure-activity relationship analysis by estimating the contributions of R-groups. Instead of attributing the activities to individual input features, MolSHAP regards the R-group fragments as the basic units of interpretation, which is in accordance with the fragment-based modifications in molecule optimization. MolSHAP is a model-agnostic method that can interpret activity regression models with arbitrary input formats and model architectures. Based on the evaluations of numerous representative activity regression models on a specially designed R-group ranking task, MolSHAP achieved significantly better interpretation power compared with other methods. In addition, we developed a compound optimization algorithm based on MolSHAP and illustrated the reliability of the optimized compounds using an independent case study. These results demonstrated that MolSHAP can provide a useful tool for accurately interpreting the quantitative structure-activity relationships and rationally optimizing the compound activities in drug discovery.

A machine learning-based framework for modeling transcription elongation.

RNA polymerase II (Pol II) generally pauses at certain positions along gene bodies, thereby interrupting the transcription elongation process, which is often coupled with various important biological functions, such as precursor mRNA splicing and gene expression regulation. Characterizing the transcriptional elongation dynamics can thus help us understand many essential biological processes in eukaryotic cells. However, experimentally measuring Pol II elongation rates is generally time and resource consuming. We developed PEPMAN (polymerase II elongation pausing modeling through attention-based deep neural network), a deep learning-based model that accurately predicts Pol II pausing sites based on the native elongating transcript sequencing (NET-seq) data. Through fully taking advantage of the attention mechanism, PEPMAN is able to decipher important sequence features underlying Pol II pausing. More importantly, we demonstrated that the analyses of the PEPMAN-predicted results around various types of alternative splicing sites can provide useful clues into understanding the cotranscriptional splicing events. In addition, associating the PEPMAN prediction results with different epigenetic features can help reveal important factors related to the transcription elongation process. All these results demonstrated that PEPMAN can provide a useful and effective tool for modeling transcription elongation and understanding the related biological factors from available high-throughput sequencing data.

Origin differentiation based on volatile constituents of genuine medicinal materials Quisqualis indica L. via HS-GC-MS, response surface methodology, and chemometrics.

INTRODUCTION: Quisqualis indica L. (QIL) has a long history as a traditional Chinese herb in China, but the study of volatile components in QIL from different geographical sources has been relatively rare. OBJECTIVES: To establish an optimal headspace gas chromatography-mass spectrometry (HS-GC-MS) method to comprehensively analyse the volatile component profile and screen quality markers of QIL from different origins. METHODS: Response surface methodology (RSM) was used to optimise the conditions for headspace analysis. The volatile components of QIL from four main origins of southwest China were analysed and identified by HS-GC-MS. The similarity of all samples of QIL was evaluated by fingerprint. The differences of the volatile components in QIL from different origins were distinguished by chemometrics. RESULTS: According to the optimal conditions of RSM, a total of 31 volatile components were identified, including fatty acids, aldehydes, alcohols, alkyl pyrazines, and other volatile components. Similarity evaluation presented that there were 26 common volatile components with different contents in all samples. Principal component analysis (PCA) showed that QIL from four different origins could be roughly divided into four categories. Hierarchical cluster analysis (HCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) indicated that QIL from different origins had obvious regional characteristics. CONCLUSION: The optimised HS-GC-MS method provided a strategy to rapidly, effectively, and accurately elucidate the volatile component profile of QIL from different origins, and seven important differential components were screened for quality evaluation and origin traceability.

Tumour-derived small extracellular vesicles contribute to the tumour progression through reshaping the systemic immune macroenvironment.

BACKGROUND: Tumour-derived small extracellular vesicles (sEVs) play a crucial role in cancer immunomodulation. In addition to tumour immune microenvironment, the peripheral immune system also contributes significantly to cancer progression and is essential for anticancer immunity. However, a comprehensive definition of which and how peripheral immune lineages are regulated by tumour-derived sEVs during cancer development remains incomplete. METHODS: In this study, we used mass cytometry with extensive antibody panels to comprehensively construct the systemic immune landscape in response to tumour development and tumour-derived sEVs. RESULTS: Systemic immunity was dramatically altered by tumour growth and tumour-derived sEVs. Tumour-derived sEVs significantly and extensively affected immune cell population composition as well as intracellular pathways, resulting in an immunosuppressive peripheral and tumour immune microenvironment, characterised by increased myeloid-derived suppressor cells and decreased Ly6C+CD8 T cells. These sEVs largely promoted hematopoietic recovery and accelerate the differentiation towards myeloid-derived suppressor cells. The knockdown of Rab27a reduced sEV secretion from tumour cells and delayed tumour growth and metastasis in vivo. CONCLUSIONS: These results highlight that tumour-derived sEVs function as a bridge between peripheral immunity regulation and the tumour microenvironment, and contribute to cancer progression through altering the composition and function of the global immune macroenvironment.

Full-length ribosome density prediction by a multi-input and multi-output model.

Translation elongation is regulated by a series of complicated mechanisms in both prokaryotes and eukaryotes. Although recent advance in ribosome profiling techniques has enabled one to capture the genome-wide ribosome footprints along transcripts at codon resolution, the regulatory codes of elongation dynamics are still not fully understood. Most of the existing computational approaches for modeling translation elongation from ribosome profiling data mainly focus on local contextual patterns, while ignoring the continuity of the elongation process and relations between ribosome densities of remote codons. Modeling the translation elongation process in full-length coding sequence (CDS) level has not been studied to the best of our knowledge. In this paper, we developed a deep learning based approach with a multi-input and multi-output framework, named RiboMIMO, for modeling the ribosome density distributions of full-length mRNA CDS regions. Through considering the underlying correlations in translation efficiency among neighboring and remote codons and extracting hidden features from the input full-length coding sequence, RiboMIMO can greatly outperform the state-of-the-art baseline approaches and accurately predict the ribosome density distributions along the whole mRNA CDS regions. In addition, RiboMIMO explores the contributions of individual input codons to the predictions of output ribosome densities, which thus can help reveal important biological factors influencing the translation elongation process. The analyses, based on our interpretable metric named codon impact score, not only identified several patterns consistent with the previously-published literatures, but also for the first time (to the best of our knowledge) revealed that the codons located at a long distance from the ribosomal A site may also have an association on the translation elongation rate. This finding of long-range impact on translation elongation velocity may shed new light on the regulatory mechanisms of protein synthesis. Overall, these results indicated that RiboMIMO can provide a useful tool for studying the regulation of translation elongation in the range of full-length CDS.

Edaravone Dexborneol Versus Edaravone Alone for the Treatment of Acute Ischemic Stroke: A Phase III, Randomized, Double-Blind, Comparative Trial.

BACKGROUND AND PURPOSE: Edaravone dexborneol, comprised of 2 active ingredients, edaravone and (+)-borneol, has been developed as a novel neuroprotective agent with synergistic effects of antioxidant and anti-inflammatory in animal models. The present clinical trial aimed at testing the effects of edaravone dexborneol versus edaravone on 90-day functional outcome in patients with acute ischemic stroke (AIS). METHODS: A multicenter, randomized, double-blind, comparative, phase III clinical trial was conducted at 48 hospitals in China between May 2015 and December 2016. Inclusion criteria included patients diagnosed as AIS, 35 to 80 years of age, National Institutes of Health Stroke Scale Score between 4 and 24, and within 48 hours of AIS onset. AIS patients were randomized in 1:1 ratio into 2 treatment arms: 14-day infusion of edaravone dexborneol or edaravone injection. The primary end point was the proportion of patients with modified Rankin Scale score ≤1 on day 90 after randomization. RESULTS: One thousand one hundred sixty-five AIS patients were randomly allocated to the edaravone dexborneol group (n=585) or the edaravone group (n=580). The edaravone dexborneol group showed significantly higher proportion of patients experiencing good functional outcomes on day 90 after randomization, compared with the edaravone group (modified Rankin Scale score ≤1, 67.18% versus 58.97%; odds ratio, 1.42 [95% CI, 1.12-1.81]; P=0.004). The prespecified subgroup analyses indicated that a greater benefit was observed in female patients than their male counterparts (2.26, 1.49-3.43 versus 1.14, 0.85-1.52). CONCLUSIONS: When edaravone dexborneol versus edaravone was administered within 48 hours after AIS, 90-day good functional outcomes favored the edaravone dexborneol group, especially in female patients. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02430350.

Pseudoneutrophil Cytokine Sponges Disrupt Myeloid Expansion and Tumor Trafficking to Improve Cancer Immunotherapy.

Myeloid-derived suppressor cells (MDSCs) promote tumor immune escape through multiple mechanisms including suppressing antitumor activities of T lymphocytes. However, therapeutic abrogation of MDSCs often causes severe adverse effects, compensatory recruitment of alternative cell populations, and the multiplicity and complexity of relevant cytokines/receptors. Alternatively, suppressing the expansion and tumor trafficking of MDSCs may be a proficient and safe way for cancer treatment. Here we report that pseudoneutrophil cytokine sponges (pCSs) can disrupt expansion and tumor trafficking of MDSCs and reverse immune tolerance. Coated with plasma membranes of neutrophils phenotypically and morphologically similar to polymorphonuclear MDSCs (PMN-MDSCs), the nanosized pCSs inherited most membrane receptors from the "parental" neutrophils, enabling the neutralization of MDSC-related cytokines. Upon pCSs administration, the expansion of MDSCs and their enrichment in peripheral lymphoid organs and tumors were reduced without the compensatory influx of alternative myeloid subsets. In murine breast cancer and melanoma syngeneic models, pCSs treatment dramatically increased the number of tumor-infiltrating T lymphocytes and restored their antitumor functions. In addition, when pCSs were combined with the programmed cell death protein 1 (PD-1), the immune checkpoint blockade synergistically suppressed tumor progression and prolonged animal survival. Overall, the pseudocell nanoplatform opens up new paths toward effective cancer immunotherapy.

Fluorescent Metallacycle-Cored Amphiphilic Nanoparticles Formed by ß-Cyclodextrin-Based Host-Guest Interactions towards Cancer Theranostics.

Theranostic agents, taking the advantages of both imaging and therapeutic functions, are anticipated to be key components in the development of personalized medicine in which the therapeutic response can be real-time monitored. Herein, three metallacycles with pendent adamantane groups are prepared by coordination-driven self-assembly of PtII ligands with anticancer activities and tetraphenylethylene derivatives with emission. ß-Cyclodextrin, which shows good host-guest interactions with adamantane moieties, was added to form amphiphilic supramolecular nanoparticles with the aim to enhance the aqueous solubilities and bioactivities of these metallacycles. Moreover, when rhodamine-modified ß-cyclodextrin was used as the carrier, the release of the metallacycles from the nanoparticles could be monitored in situ through the fluorescence changes owing to the efficient fluorescence resonance energy transfer from the metallacycles to rhodamine-modified ß-cyclodextrin. In vitro and in vivo studies showed that these nanoparticles not only served as cell imaging contrast agents but also displayed improved anticancer activities, allowing them to serve as potential candidates for cancer theranostics. This study provides a simple and efficient method to prepare theranostic agents by hierarchical supramolecular self-assembly, which will pave the way for image-guided cancer therapy, targeted cancer therapy, and related biomedical fields.

A deep boosting based approach for capturing the sequence binding preferences of RNA-binding proteins from high-throughput CLIP-seq data.

Characterizing the binding behaviors of RNA-binding proteins (RBPs) is important for understanding their functional roles in gene expression regulation. However, current high-throughput experimental methods for identifying RBP targets, such as CLIP-seq and RNAcompete, usually suffer from the false negative issue. Here, we develop a deep boosting based machine learning approach, called DeBooster, to accurately model the binding sequence preferences and identify the corresponding binding targets of RBPs from CLIP-seq data. Comprehensive validation tests have shown that DeBooster can outperform other state-of-the-art approaches in RBP target prediction. In addition, we have demonstrated that DeBooster may provide new insights into understanding the regulatory functions of RBPs, including the binding effects of the RNA helicase MOV10 on mRNA degradation, the potentially different ADAR1 binding behaviors related to its editing activity, as well as the antagonizing effect of RBP binding on miRNA repression. Moreover, DeBooster may provide an effective index to investigate the effect of pathogenic mutations in RBP binding sites, especially those related to splicing events. We expect that DeBooster will be widely applied to analyze large-scale CLIP-seq experimental data and can provide a practically useful tool for novel biological discoveries in understanding the regulatory mechanisms of RBPs. The source code of DeBooster can be downloaded from http://github.com/dongfanghong/deepboost.

Fluorescent metallacycle-cored polymers via covalent linkage and their use as contrast agents for cell imaging.

The covalent linkage of supramolecular monomers provides a powerful strategy for constructing dynamic polymeric materials whose properties can be readily tuned either by the selection of monomers or the choice of functional linkers. In this strategy, the stabilities of the supramolecular monomers and the reactions used to link the monomers are crucial because such monomers are normally dynamic and can disassemble during the linking process, leading to mixture of products. Therefore, although noncovalent interactions have been widely introduced into metallacycle structures to prepare metallosupramolecular polymers, metallacycle-cored polymers linked by covalent bonds have been rarely reported. Herein, we used the mild, highly efficient amidation reaction between alkylamine and N-hydroxysuccinimide-activated carboxylic acid to link the pendent amino functional groups of a rhomboidal metallacycle 10 to give metallacycle-cored polymers P1 and P2, which further yielded nanoparticles at low concentration and transformed into network structures as the concentration increased. Moreover, these polymers exhibited enhanced emission and showed better quantum yields than metallacycle 10 in methanol and methanol/water (1/9, vol/vol) due to the aggregation-induced emission properties of a tetraphenylethene-based pyridyl donor, which serves as a precursor for metallacycle 10. The fluorescence properties of these polymers were further used in cell imaging, and they showed a significant enrichment in lung cells after i.v. injection. Considering the anticancer activity of rhomboidal Pt(II) metallacycles, this type of fluorescent metallacycle-cored polymers can have potential applications toward lung cancer treatment.

Enzyme Degradable Hyperbranched Polyphosphoester Micellar Nanomedicines for NIR Imaging-Guided Chemo-Photothermal Therapy of Drug-Resistant Cancers.

Multidrug resistance (MDR) is the major cause for chemotherapy failure, which constitutes a formidable challenge in the field of cancer therapy. The synergistic chemo-photothermal treatment has been reported to be a potential strategy to overcome MDR. In this work, rationally designed enzyme-degradable, hyperbranched polyphosphoester nanomedicines were developed for reversing MDR via the codelivery of doxorubicin and IR-780 (hPPEDOX&IR) as combined chemo-photothermal therapy. The amphiphilic hyperbranched polyphosphoesters with phosphate bond as the branching point were synthesized via a simple but robust one-step polycondensation reaction. The self-assembled hPPEDOX&IR exhibited good serum stability, sustained release, preferable tumor accumulation, and enhanced drug influx of doxorubicin in resistant MCF-7/ADR cells. Moreover, the degradation of hPPEDOX&IR was accelerated in the presence of alkaline phosphatase, which was overexpressed in various cancers, resulting in the fast release of encapsulated doxorubicin. The enzyme-degradable polymer generated synergistic chemo-photothermal cytotoxicity against MCF-7/ADR cells and, thus, the efficient ablation of DOX-resistant tumor without regrowth. This delivery system may open a new avenue for codelivery of chemo- and photothermal therapeutics for MDR tumor therapy.

Low- versus Standard-Dose Intravenous Tissue-Type Plasminogen Activator for Acute Ischemic Stroke: An Updated Meta-Analysis.

BACKGROUND: We performed a meta-analysis to compare the efficacy and safety between low- and standard-dose intravenous (IV) tissue-type plasminogen activator (tPA) for acute ischemic stroke (AIS) patients within 4.5 hours of symptom onset. METHODS: We searched PubMed and EMBASE for relevant studies from inception to June1, 2017. Cohort or randomized controlled studies for AIS within 4.5 hours of symptom onset with comparison between low-dose and standard-dose tPA were included. The primary efficacy end point was favorable functional outcome (modified Rankin scale scores [mRS] of 0-1) at 90 days. The primary safety end point was the incidence rate of symptomatic intracerebral hemorrhage (sICH). The secondary end points were independent functional outcome (mRS scores of 0-2) and mortality. RESULTS: A total of 11 studies were pooled in this meta-analysis. The low-dose strategy appeared to be as effective as standard-dose tPA (43.4% versus 45.4%; odds ratio [OR] = 0.93, 95% confidence interval [CI]: 0.78-1.10; P = .38) in primary efficacy outcome. The secondary efficacy outcome produced similar results (57.3% versus 57.0%; OR = 0.95, 95% CI: 0.86-1.05; P= .33). There was no evidence of statistical difference for sICH (4.2% versus 4.9%; OR = 1.02 [0.66-1.55]; P = .94) and mortality (9.0% versus 10.6%; OR = 0.99 [0.74-1.31]; P = .92) at 90 days between low- and standard-dose therapy. In a subgroup analysis by ethnicity, there was no significant difference between patients of Asian and non-Asian descent for any of the end points. CONCLUSIONS: This study showed that AIS patients receiving low-dose IV-tPA had comparably efficacy and safety to those receiving standard-dose IV-tPA. However, the effect is especially pronounced within the Asian population, which limits the generalizability of these results.

The polymorphic CAG repeat in exon 1 of androgen receptor is associated with level of HDL cholesterol and hypertension in Chinese middle-aged and elderly men.

OBJECTIVE: The length of the CAG repeats in exon 1 of the androgen receptor (AR) gene has been shown to be inversely correlated with AR transcriptional activity. This study aimed to investigate the correlations between the length of CAG repeat in AR and serum lipids and hypertension in Chinese men. DESIGN AND PATIENTS: The relationship between length of the CAG repeat in exon 1 of AR with prevalence of hypertension and the levels of serum lipids among Chinese men (aged ≥40 years). MEASUREMENTS: The physical condition of the subjects was examined and recorded. The concentrations of blood lipids and sex hormones were measured, and the CAG repeat lengths of the AR gene were determined. RESULTS: The length of the AR CAG repeats was associated with HDL cholesterol (HDL-C) concentration, and the stepwise multiple regression model showed that this association was independent of body mass index (BMI), triglycerides (TG) and total cholesterol (TC), although these factors influence HDL-C concentration. Furthermore, men with <22 vs men with ≥22 CAG repeats showed higher blood pressure and higher prevalence of hypertension. Shorter CAG repeat numbers were associated with the increased risk of hypertension in a multivariate logistic regression analysis (odds ratio = 0·715; 95% confidence interval, 0·517-0·989; P = 0·043). No significant correlation of AR CAG repeat polymorphism with sex hormone levels, TG, LDL cholesterol (LDL-C) or TC was found. CONCLUSIONS: This study provides evidence that men carrying shorter (<22) AR CAG repeats have lower HDL-C level and increased risk of hypertension. The androgenic activity may differ due to the polymorphic length of CAG repeats of the AR gene.

Understanding the Capsanthin Tails in Regulating the Hydrophilic-Lipophilic Balance of Carbon Dots for a Rapid Crossing Cell Membrane.

Here we use natural Chinese paprika to prepare a new kind of amphiphilic carbon dot (A-Dot) that exhibits bright, multicolored fluorescence and contains hydrophilic groups as well as lipophilic capsanthin tails on the surface. It is found that the capsanthin tails in a phospholipid-like structure can promote cell internalization of the A-Dots via crossing cell membranes rapidly in an energy-independent fashion. Compared to highly hydrophilic carbon dots (H-Dots), a control sample prepared from the microwave thermolysis of citric acid and ethylenediamine, our synthesized A-Dots can be taken up by CHO, HeLa, and HFF cells more easily. More importantly, we develop a method to calibrate the hydrophilic-lipophilic balance (HLB) values of various kinds of carbon dots (C-Dots). HLB values of A-Dots and H-Dots are determined to be 6.4 and 18.4, respectively. Moreover, we discover that the cellular uptake efficiency of C-Dots is closely related to their HLBs, and the C-Dots with an HLB value of around 6.4 cross the cell membrane easier and faster. As we regulate the HLB value of the A-Dots from 6.4 to 15.3 by removing the capsanthin tails from their surfaces via alkali refluxing, it is found that the refluxed A-Dots can hardly cross HeLa cell membranes. Our work is an essential step toward understanding the importance of regulating the HLB values as well as the surface polarity of the C-Dots for their practical use in bioimaging and also provides a simple but effective way to judge whether the C-Dots in hand are appropriate for cell imaging.

Atrial fibrillation is not uncommon among patients with ischemic stroke and transient ischemic stroke in China.

BACKGROUND: Atrial fibrillation (AF) is reported to be a less frequent cause of ischemic stroke in China than in Europe and North America, but it is not clear whether this is due to underestimation. Our aim was to define the true frequency of AF-associated stroke, to determine the yield of 6-day Holter ECG to detect AF in Chinese stroke patients, and to elucidate predictors of newly detected AF. METHODS: Patients with acute ischemic stroke or transient ischemic attack (TIA) were enrolled in a prospective, multicenter cohort study of 6-day Holter monitoring within 7 days after stroke onset at 20 sites in China between 2013 and 2015. Independent predictors of newly-detected AF were determined by multivariate analysis. RESULTS: Among 1511 patients with ischemic stroke and TIA (mean age 63 years, 33.1% women), 305 (20.2%) had either previously known (196, 13.0%) or AF newly-detected by electrocardiography (53, 3.5%) or by 6-day Holter monitoring (56/1262, 4.4%). A history of heart failure (OR = 4.70, 95%CI, 1.64-13.5), advanced age (OR = 1.06, 95%CI, 1.04-1.09), NIHSS at admission (OR = 1.06, 95%CI, 1.02-1.10), blood high density lipoprotein (HDL) (OR = 1.52, 95%CI, 1.09-2.13), together with blood triglycerides (OR = 0.64, 95%CI, 0.45-0.91) were independently associated with newly-detected AF. CONCLUSIONS: Contrary to previous reports, AF-associated stroke is frequent (20%) in China if systemically sought. Prolonged noninvasive cardiac rhythm monitoring importantly increases AF detection in patients with recent ischemic stroke and TIA in China. Advanced age, history of heart failure, and higher admission NIHSS and higher level of HDL were independent indicators of newly-detected AF. TRIAL REGISTRATION: NCT02156765 (June 5, 2014).

[Association of Insulin Resistance and ß Cell Function with Lipid Metabolism in Middle-aged and Elderly Hui and Han Populations].

OBJECTIVE: To explore the association of insulin resistance and ß cell function with lipid metabolism in middle-aged and elderly Hui and Han populations. METHODS: A total of 1000 subjects age over 40 years were recruited from five urban communities in Yinchuan and Wuzhong cities of Ningxia. The composition ratio between Hui and Han nationality was 1:2. A questionnaire-based survey was performed. Physical examinations were carried out to measure the height, body mass, waistline, and hipline. The levels of triglyceride (TG), total cholesterol (TC), blood uric acid (BUA), fasting blood glucose and insulin were measured. The boby mass index (BMI), waist-hip ratio (WHR), and secretion related index including insulin resistance index (IR), insulin sensitivity index (IAI), and beta cell function index (HBCI) were calculated. RESULTS: The BMI, WHR, IAI, HBCI, and the prevalence rate of diabetes in Hui nationality were significantly higher than those in Han nationality (P<0.01). The levels of BUA, fasting blood glucose, TC, and IR in Han nationality were significantly lower than those in Hui nationality (P<0.01). In Hui populations, TG, BMI, WHR, and BUA were positively correlated with IR (r=0.234, r=0.193, r=0.143, and r=0.129, respectively; P<0.01) and were negatively correlated with IAI (r=-0.234, r=-0.193, r=-0.143, r=-0.129, respectively; P<0.01), whereas TC was negatively correlated with HBCI (r=-0.169, P<0.01). In Han populations, TC, TG, BMI, WHR, and BUA were positively correlated with IR (r=0.140, r=0.257, r=0.288, r=0.163, r=0.104, P<0.01) and negatively correlated with IAI (r=-0.140, r=-0.257, r=-0.288, r=-0.163, and r=-0.104, P<0.01), whereas BMI was negatively correlated with HBCI (r=-0.111, P<0.01). After the influential factors such as gender, nationality, and age were adjusted, the TC, TG, BMI, WHR, BUA levels were positively correlated with IR (r=0.109, r=0.256, r=0.253, r=0.139, and r=0.142, P<0.01) and negatively correlated with IAI (r=-0.109, r=-0.256, r=-0.253, r=-0.139, and r=-0.142, P<0.01). TC and BMI were negatively correlated with HBCI (r=-0.113, r=-0.086, P<0.01). TG and BMI were independently associated with IR and IAI (r=0.218, r=0.182, r=-0.218, r=-0.182), while TC and BMI were independently associated with HBCI (r=-0.113, r=-0.086). CONCLUSIONS: The distributions of TC, TG, BMI, WHR, BUA, IR, IAI, and HBCI differ between Han and Hui populations. The development of insulin resistance is closely related with the increased levels of TC, TG, BMI, WHR, and BUA. However, the HBCI increases with the increased level of TC and BMI. TG and BMI may be related with insulin resistance. Also, TC and BMI may affect the secretion function of ß cells.

[Inhibitory effect on Microcystis aeruginosa as well as separation and identification of the allelochemicals of Allium cepa].

OBJECTIVE: To uncover the inhibition of Allium cepa (onion) on Microcystis aeruginosa, and identify the allelochemicals in onion. METHODS: The inhibition of different concentrations of onion bulb and onion leaf water extracts on M. aeruginosa were investigated, and the allelochemicals of onion bulb were extracted and identified by organic solvent and GC-MS, repectively. RESULTS: Both onion bulb and onion leaf water extracts had, to different degree, inhibitory effect on the growth of M. aeruginosa. Compared with the control group, the onion bulb and onion leaf extracts treatment groups were lower than the control group in the same period, and the inhibitory effect were more obvious with the increase of the water extract concentrations. The inhibition ratios of water extracts from onion bulb to M. aeruginosat were 100% on the fifth day, except 5 ml/L water extract treatment group. And the inhibition ratio of 40 ml/L water extract treatment group from onion leaf to M. aeruginosat was 97. 4% on the sixth day. The main allelochemicals in onion includes tris (hydroxymethyl) nitromethane, nonanoic acid, capric acid and methane sulfonic anhydride. CONCLUSION: The inhibition of onion bulb water extracts on Microcystis aeruginosa are very strong and better than onion leaf water extracts.