Publications by authors named "Zijun Chen"

71 Publications

Time-Crystalline Eigenstate Order on a Quantum Processor.

Nature 2021 Nov 30. Epub 2021 Nov 30.

Google Research, Mountain View, CA, USA.

Quantum many-body systems display rich phase structure in their low-temperature equilibrium states. However, much of nature is not in thermal equilibrium. Remarkably, it was recently predicted that out-of-equilibrium systems can exhibit novel dynamical phases that may otherwise be forbidden by equilibrium thermodynamics, a paradigmatic example being the discrete time crystal (DTC). Concretely, dynamical phases can be defined in periodically driven many-body localized (MBL) systems via the concept of eigenstate order. In eigenstate-ordered MBL phases, the entire many-body spectrum exhibits quantum correlations and long-range order, with characteristic signatures in late-time dynamics from all initial states. It is, however, challenging to experimentally distinguish such stable phases from transient phenomena, or from regimes in which the dynamics of few select states can mask typical behavior. Here we implement tunable CPHASE gates on an array of superconducting qubits to experimentally observe an MBL-DTC and demonstrate its characteristic spatiotemporal response for generic initial states. Our work employs a time-reversal protocol to quantify the impact of external decoherence, and leverages quantum typicality to circumvent the exponential cost of densely sampling the eigenspectrum. Furthermore, we locate the phase transition out of the DTC with an experimental finite-size analysis. These results establish a scalable approach to studying non-equilibrium phases of matter on quantum processors.
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http://dx.doi.org/10.1038/s41586-021-04257-wDOI Listing
November 2021

Absolute Structure Determination and Kv1.5 Ion Channel Inhibition Activities of New Debromoaplysiatoxin Analogues.

Mar Drugs 2021 Nov 11;19(11). Epub 2021 Nov 11.

Department of Development Technology of Marine Resources, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China.

Potassium channel Kv1.5 has been considered a key target for new treatments of atrial tachyarrhythmias, with few side effects. Four new debromoaplysiatoxin analogues with a 6/6/12 fused ring system were isolated from marine cyanobacterium sp. Their planar structures were elucidated by HRESIMS, 1D and 2D NMR. The absolute configuration of oscillatoxin J () was determined by single-crystal X-ray diffraction, and the absolute configurations of oscillatoxin K (), oscillatoxin L () and oscillatoxin M () were confirmed on the basis of GIAO NMR shift calculation followed by DP4 analysis. The current study confirmed the absolute configuration of the pivotal chiral positions (7S, 9S, 10S, 11R, 12S, 15S, 29R and 30R) at traditional ATXs with 6/12/6 tricyclic ring system. Compound , and exhibited blocking activities against Kv1.5 with IC values of 2.61 ± 0.91 µM, 3.86 ± 1.03 µM and 3.79 ± 1.01 µM, respectively. However, compound exhibited a minimum effect on Kv1.5 at 10 µM. Furthermore, all of these new debromoaplysiatoxin analogs displayed no apparent activity in a brine shrimp toxicity assay.
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http://dx.doi.org/10.3390/md19110630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8622842PMC
November 2021

TRIM21 regulates pyroptotic cell death by promoting Gasdermin D oligomerization.

Cell Death Differ 2021 Sep 11. Epub 2021 Sep 11.

Department of Neurology, Huashan Hospital and Institute of Neurology, State Key Laboratory of Genetic Engineering, School of Life Sciences, MOE Engineering Research Center of Gene Technology, Shanghai Engineering Research Center of Industrial Microorganisms, Fudan University, Shanghai, China.

Gasdermin-D (GSDMD), the executioner of pyroptotic cell death when it is cleaved by inflammatory caspases, plays a crucial role in host defense and the response to danger signals. So far, there are no known mechanisms, other than cleavage, for regulating GSDMD. Here, we show that tripartite motif protein TRIM21 acts as a positive regulator of GSDMD-dependent pyroptosis. TRIM21 interacted with GSDMD via its PRY-SPRY domain, maintaining GSDMD stable expression in resting cells yet inducing the N-terminus of GSDMD (GSDMD-N) aggregation during pyroptosis. TRIM21-deficient cells displayed a reduced cell death in response to NLRP3 or NLRC4 inflammasome activation. Genetic ablation of TRIM21 in mice conferred protection from LPS-induced inflammation and dextran sulfate sodium-induced colitis. Therefore, TRIM21 plays an essential role in GSDMD-mediated pyroptosis and may be a viable target for controlling and treating inflammation-associated diseases.
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http://dx.doi.org/10.1038/s41418-021-00867-zDOI Listing
September 2021

Rural and Female Patients with Old Myocardial Infarction Lacked Knowledge and Preventive Measures During the Beginning of the COVID-19 Epidemic in Chongqing, Southwest China.

Med Sci Monit 2021 Sep 13;27:e928512. Epub 2021 Sep 13.

Department of Cardiology, Yongchuan Hospital of Chongqing Medical University, Chongqing, China (mainland).

BACKGROUND Coronavirus disease 2019 (COVID-19) has emerged as a global threat. This study was performed to gain an understanding of COVID-19-related knowledge, attitudes, and practices among susceptible individuals. MATERIAL AND METHODS Patients who had been diagnosed with old myocardial infarction were followed up via telephone survey based on an established follow-up system at the beginning of the COVID-19 outbreak (January 2020) in Chongqing, Southwest China. RESULTS A total of 631 eligible patients participated in this survey, and 40.6% of the rural respondents did not know the transmission routes of SARS-CoV-2, which was higher than the proportion of urban respondents (40.6% vs 31.0). Rural residents had a lower rate of adopting preventive measures than urban residents, such as wearing masks (76.7% vs 90.1%), avoiding meetings and gatherings (58.6% vs 68.5%), and hand washing (56.0% vs 63.8%). A higher percentage of women than men did not take any preventive measures (11.3% vs 7.6%), while a lower percentage of women than men wore masks (77.7% vs 84.5%). Multiple logistic regression revealed that rural patients were more likely to lack knowledge about transmission (odds ratio (OR): 1.51). Rural patients had an increased risk of failing to implement protective measures. CONCLUSIONS Female and rural populations lacked knowledge and failed to adopt protective measures during the beginning of the COVID-19 epidemic. Therefore, these populations may benefit from health education campaigns and policies.
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http://dx.doi.org/10.12659/MSM.928512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448519PMC
September 2021

Copper-Mediated Radiosynthesis of [F]Rucaparib.

Org Lett 2021 09 30;23(18):7290-7294. Epub 2021 Aug 30.

Chemistry Research Laboratory, Oxford University, Oxford OX1 3TA, U.K.

The poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib is used in the clinic to treat -mutated cancers. Herein, we report two strategies to access the F-isotopologue of rucaparib by applying a copper-mediated nucleophilic F-fluorodeboronation. The most successful approach features an aldehydic boronic ester precursor that is subjected to reductive amination post-F-labeling and affords [F]rucaparib with an activity yield of 11% ± 3% ( = 3) and a molar activity () up to 30 GBq/μmol. Preliminary studies are presented.
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http://dx.doi.org/10.1021/acs.orglett.1c02770DOI Listing
September 2021

The tectonigral pathway regulates appetitive locomotion in predatory hunting in mice.

Nat Commun 2021 07 20;12(1):4409. Epub 2021 Jul 20.

National Institute of Biological Sciences, Beijing, China.

Appetitive locomotion is essential for animals to approach rewards, such as food and prey. The neuronal circuitry controlling appetitive locomotion is unclear. In a goal-directed behavior-predatory hunting, we show an excitatory brain circuit from the superior colliculus (SC) to the substantia nigra pars compacta (SNc) to enhance appetitive locomotion in mice. This tectonigral pathway transmits locomotion-speed signals to dopamine neurons and triggers dopamine release in the dorsal striatum. Synaptic inactivation of this pathway impairs appetitive locomotion but not defensive locomotion. Conversely, activation of this pathway increases the speed and frequency of approach during predatory hunting, an effect that depends on the activities of SNc dopamine neurons. Together, these data reveal that the SC regulates locomotion-speed signals to SNc dopamine neurons to enhance appetitive locomotion in mice.
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http://dx.doi.org/10.1038/s41467-021-24696-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292483PMC
July 2021

Vitamin D3 reduces hippocampal NR2A and anxiety in nicotine withdrawal mice.

Transl Neurosci 2021 Jan 11;12(1):273-281. Epub 2021 Jun 11.

The First Affiliated Hospital of Anhui University of Science and Technology, Anhui Huainan 232001, China.

Nicotine withdrawal symptoms, mainly anxiety, cause high level of relapse rate after quitting smoking. Vitamin D supplementation has shown its potential for the prevention and treatment of anxiety disorders; however, neurobiological studies about the effect of vitamin D on nicotine withdrawal-induced anxiety are limited. To investigate the effect and molecular mechanism of vitamin D3 supplement by dietary on anxiety-like behavior during nicotine withdrawal, male C57/BL6 mice were divided into four groups: vehicle, nicotine only, vitamin D3 only, and nicotine plus vitamin D3. Mice were administrated with nicotine in drinking water (200 µg/mL), and vitamin D3 in feed for 6 weeks. During nicotine withdrawal, vitamin D3-treated mice showed significantly less anxiety-like behavior by an open-field test and marble buried test that performed an increase in the duration of the central zone and a decrease buried marble, respectively. Moreover, vitamin D3 supplementation attenuated the hippocampal NR2A expression on both protein and mRNA levels in nicotine and vitamin D3-treated mice. Our data showed that dietary supplementation with vitamin D3 ameliorated nicotine withdrawal-induced anxiety, which may be related to downregulation of NR2A expression in hippocampus. Vitamin D3 may provide a new dietary intervention with the easy access for smoking cessation.
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http://dx.doi.org/10.1515/tnsci-2020-0166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200643PMC
January 2021

Serum Uric Acid Revealed a U-Shaped Relationship With All-Cause Mortality and Cardiovascular Mortality in High Atherosclerosis Risk Patients: The ASSURE Study.

Front Cardiovasc Med 2021 24;8:641513. Epub 2021 May 24.

Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.

Previous studies have demonstrated an association between hyperuricemia and cardiovascular disease (CVD). The Framingham study confirmed that patients with high atherosclerotic risks (HARs) had worse prognoses. However, after adjusting for confounding factors, the association between serum uric acid (SUA) and all-cause mortality and cardiovascular mortality remains unclear, especially for HAR patients. The aim of this study was to reveal the relationship of SUA with all-cause and cardiovascular mortality in HAR patients. This multicenter cohort study enrolled 3,047 participants, and the follow-up was 68.85 ± 11.37 months. Factors related to cardiovascular and all-cause mortality were tested by multivariate Cox regression analysis. Restricted cubic splines (RCSs) with knots were used to explore the shape of the dose-response relationship with SUA and the hazard ratio (HR) of all-cause and CVD mortality. SUA transformed by RCS was added to the Cox regression model as an independent variable, and all-cause and CVD mortality scores were calculated. Survival receiver operating characteristic curves were produced using a regression model predicting the score. SUA demonstrated a "U-shaped" relationship with all-cause and cardiovascular mortality. SUA predicted all-cause and CVD mortality, with cutoff values of values of >370.5 μmol/L for males and >327.65 μmol/L for females and <180.5 μmol/L for males and <165.7 μmol/L for females, respectively. The survival ROC curve indicated that SUA is able to predict all-cause and CVD mortality, with areas under the curve of 0.702 and 0.711, respectively. The HRs of all-cause mortality (male and female) with hyperuricemia and hypouricemia were 2.08 and 2.01 and 2.04 and 1.98, respectively, and the HRs of CVD mortality (male and female) were 2.09 and 1.79, and 2.02 and 1.89, respectively. Abnormal SUA levels were significant and independent risk factors for all-cause and CVD mortality. Hyperuricemia and hypouricemia increased mortality in both males and females. Routine SUA evaluation and intensive management are needed for HAR patients. www.ClinicalTrials.gov, identifier: NCT03616769.
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http://dx.doi.org/10.3389/fcvm.2021.641513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8180559PMC
May 2021

Effect of timing of surgical resection of primary hepatocellular carcinoma on survival outcomes in elderly patients and prediction of clinical models.

BMC Gastroenterol 2021 May 21;21(1):230. Epub 2021 May 21.

Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, China.

Background: The effect of time delay from diagnosis to surgery on the prognosis of elderly patients with liver cancer is not well known. We investigated the effect of surgical timing on the prognosis of elderly hepatocellular carcinoma patients undergoing surgical resection and constructed a Nomogram model to predict the overall survival of patients.

Methods: A retrospective analysis was performed on elderly patients with primary liver cancer after hepatectomy from 2012 to 2018. The effect of surgical timing on the prognosis of elderly patients with liver cancer was analyzed using the cut-off times of 18 days, 30 days, and 60 days. Cox was used to analyze the independent influencing factors of overall survival in patients, and a prognostic model was constructed.

Results: A total of 232 elderly hepatocellular carcinoma patients who underwent hepatectomy were enrolled in this study. The cut-off times of 18, 30, and 60 days were used. The duration of surgery had no significant effect on overall survival. Body Mass Index, Child-Pugh classification, Tumor size Max, and Length of stay were independent influencing factors for overall survival in the elderly Liver cancer patients after surgery. These factors combined with Liver cirrhosis and Venous tumor emboli were incorporated into a Nomogram. The nomogram was validated using the clinical data of the study patients, and exhibited better prediction for 1-year, 3-year, and 5-year overall survival.

Conclusions: We demonstrated that the operative time has no significant effect on delayed operation in the elderly patients with hepatocellular carcinoma, and a moderate delay may benefit some patients. The constructed Nomogram model is a good predictor of overall survival in elderly patients with hepatectomy.
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http://dx.doi.org/10.1186/s12876-021-01815-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139139PMC
May 2021

Cognition and progress of de Winter electrocardiogram pattern.

Zhong Nan Da Xue Xue Bao Yi Xue Ban 2021 Apr;46(4):421-425

Department of Cardiology, Yongchuan Hospital of Chongqing Medical University, Chongqing 402160, China.

The de Winter electrocardiogram pattern is an acute ST-segment elevation myocardial infarction equivalent, however this specific electrocardiogram change is easily ignored by clinicians. The de Winter electrocardiogram pattern in patients with acute chest pain mostly indicates sub-complete or complete occlusion of the left anterior descending or the diagonal branch. Patients with acute chest pain and such electrocardiographic finding should undergo emergency coronary angiography immediately to determine the coronary condition, and reperfusion therapy should be performed as soon as possible to reduce the incidence of adverse cardiovascular events.
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http://dx.doi.org/10.11817/j.issn.1672-7347.2021.190588DOI Listing
April 2021

From reversal to normal: Robust improvement in conflict adaptation through real-time functional near infrared spectroscopy-based neurofeedback training.

Neuropsychologia 2021 07 28;157:107866. Epub 2021 Apr 28.

Key Laboratory of Cognition and Personality of Ministry of Education, Faculty of Psychology, Southwest University, Chongqing, 400715, China. Electronic address:

Conflict adaptation refers to the improved conflict control induced after experiencing conflict and is a prominent index of adaptive cognitive control. Reversal of conflict adaptation may be maladaptive and predictive of certain mental disorders. Here, we employed real-time functional near infrared spectroscopy-based neurofeedback training, with the left dorsolateral prefrontal cortex as the target brain area, to investigate whether reversal of conflict adaptation during a word-color Stroop task could be recovered to be normal. Healthy human individuals with reversal pattern of conflict adaptation in the pretest were randomly assigned into the experimental or control groups. Distributed training for 80 min led to greater improvements in the experimental group who received real neurofeedback compared to those in the control group who received sham neurofeedback. These results indicated causal evidence for understanding the generation of conflict adaptation and heighten the prospects of clinical application of neurofeedback training.
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http://dx.doi.org/10.1016/j.neuropsychologia.2021.107866DOI Listing
July 2021

Pharmacological inhibition of SRC-1 phase separation suppresses YAP oncogenic transcription activity.

Cell Res 2021 Sep 13;31(9):1028-1031. Epub 2021 Apr 13.

Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201203, China.

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http://dx.doi.org/10.1038/s41422-021-00504-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410775PMC
September 2021

Improving Emotion Regulation Through Real-Time Neurofeedback Training on the Right Dorsolateral Prefrontal Cortex: Evidence From Behavioral and Brain Network Analyses.

Front Hum Neurosci 2021 17;15:620342. Epub 2021 Mar 17.

Key Laboratory of Cognition and Personality of Ministry of Education, Faculty of Psychology, Southwest University, Chongqing, China.

We investigated if emotion regulation can be improved through self-regulation training on non-emotional brain regions, as well as how to change the brain networks implicated in this process. During the training period, the participants were instructed to up-regulate their right dorsolateral prefrontal cortex (rDLPFC) activity according to real-time functional near-infrared spectroscopy (fNIRS) neurofeedback signals, and there was no emotional element. The results showed that the training significantly increased emotion regulation, resting-state functional connectivity (rsFC) within the emotion regulation network (ERN) and frontoparietal network (FPN), and rsFC between the ERN and amygdala; however, training did not influence the rsFC between the FPN and the amygdala. However, self-regulation training on rDLPFC significantly improved emotion regulation and generally increased the rsFCs within the networks; the rsFC between the ERN and amygdala was also selectively increased. The present study also described a safe approach that may improve emotion regulation through self-regulation training on non-emotional brain regions.
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http://dx.doi.org/10.3389/fnhum.2021.620342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010650PMC
March 2021

Causal effects of plasma lipids on the risk of atrial fibrillation: A multivariable mendelian randomization study.

Nutr Metab Cardiovasc Dis 2021 05 20;31(5):1569-1578. Epub 2021 Feb 20.

Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. Electronic address:

Background And Aims: Observational studies have suggested that plasma lipids contribute substantially to cardiovascular disease, but "cholesterol paradox" in atrial fibrillation (AF) remains. We sought to investigate the causal effects of lipid profiles on the risk of AF.

Methods And Results: Two-sample Mendelian randomization (MR) framework was implemented to examine the causality of association. Summary estimations of genetic variants associated with low density lipoprotein (LDL)-cholesterol, high density lipoprotein (HDL)-cholesterol, total cholesterol, triglycerides, lipoprotein-a [Lp(a)], apolipoprotein A1 (ApoA 1), and apolipoprotein B (ApoB) were 81, 99, 96, 61, 30, 10, and 23 single nucleotide polymorphisms, respectively. Genetic association with AF were retrieved from a genome-wide association study that included 1,030,836 individuals. The complications for AF were predefined as cardioembolic stroke (CES) and heart failure (HF). In the multivariable MR, the odds ratios for AF per standard deviation (SD) increase were 1.030 (95% confidence interval (CI) 0.979-1.083; P = 0.257) for LDL-cholesterol, 0.986 (95% CI 0.931-1.044; P = 0.622) for HDL-cholesterol, 0.965 (95% CI 0.896-1.041; P = 0.359) for triglycerides, 1.001 (95% CI 1.000-1.003; P = 0.023) for Lp(a), 1.017 (95% CI 0.966-1.070; P = 0.518) for ApoA1, and 1.002 (95% CI 0.963-1.043; P = 0.923) for ApoB. There was no evidence that other lipid components were causally associated with AF, CES, or HF, other than for a marginal association between triglycerides and HF.

Conclusions: This MR study provides robust evidence that high Lp(a) increases the risk of AF, suggesting that interventions targeting Lp(a) may contribute to the primary prevention of AF.
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http://dx.doi.org/10.1016/j.numecd.2021.02.011DOI Listing
May 2021

Serum Levels of FGF21, β-Klotho, and BDNF in Stable Coronary Artery Disease Patients With Depressive Symptoms: A Cross-Sectional Single-Center Study.

Front Psychiatry 2020 21;11:587492. Epub 2021 Jan 21.

Comprehensive Laboratory, The Third Affiliated Hospital of Soochow University, Changzhou, China.

The incidence of depressive symptoms (DS) in patients with stable coronary artery disease (SCAD) is significantly higher than those in healthy population, and that DS are independent risk factors for cardiovascular events. Previous studies have reported that fibroblast growth factor 21 (FGF21), β-klotho, mature brain-derived neurotrophic factor (mBDNF), and BDNF precursor (proBDNF) play important roles in the pathogenesis and treatment of coronary heart disease and depression. With this in mind, the present study aimed to clarify the relationship between FGF21, β-klotho, mBDNF, and proBDNF and SCAD with comorbid depression, in addition to also exploring the underlying mechanisms of these disease processes. A total of 116 patients with SCAD and 45 healthy controls were recruited. Patients with SCAD were further divided into two subgroups based on the Zung Self-Rating Depression Scale (SDS), which were characterized as those with no DS (NDS) and those with DS. Baseline data were collected, and serum levels of FGF21, β-klotho, mBDNF, and proBDNF were determined. In SCAD patients, Gensini scores-denoting the degree of coronary arteriostenosis-were significantly greater in the DS group than in the NDS group. There was also a positive correlation between the Gensini scores and the SDS scores. Patients in the SCAD group demonstrated a lower serum FGF21. Serum β-klotho, mBDNF, and mBDNF/proBDNF were also significantly lower in the DS group than in the NDS group. Furthermore, β-klotho and mBDNF were negatively correlated with the SDS scores. Additionally, SCAD patients were divided into lower- and higher-level groups using hierarchical cluster analysis, with the results highlighting that patients in the lower mBDNF group had a higher incidence of DS. The depression score was positively correlated with the severity of coronary artery stenosis, and serum FGF21, β-klotho, mBDNF, and proBDNF were closely related to the development of DS in patients with SCAD. These observations suggest FGF21, β-klotho, mBDNF, and proBDNF as potential diagnostic and/or therapeutic targets for SCAD with co-morbid depression.
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http://dx.doi.org/10.3389/fpsyt.2020.587492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873935PMC
January 2021

Clinical characteristics of patients with the de Winter electrocardiogram pattern.

Zhong Nan Da Xue Xue Bao Yi Xue Ban 2020 Dec;45(12):1431-1436

Department of Cardiology, Yongchuan Hospital of Chongqing Medical University, Chongqing 402160, China.

Objectives: To explore the electrocardiogram manifestations and clinical characteristics of patients with the de Winter electrocardiogram pattern.

Methods: This retrospective study was performed on acute coronary syndrome (ACS), patients with culprit lesion in left anterior descending branch (LAD), who admitted to Yongchuan Hospital of Chongqing Medical University from August 2017 to October 2018. Patients were categorized into those with or without the de Winter electrocardiogram pattern. The characteristics of de Winter electrocardiogram were analyzed by the clinical data of the patients.

Results: Among 230 patients with left anterior descending branch lesion, 14 (6%) had the de Winter electrocardiogram pattern. Compared with the control group, patients with de Winter electrocardiogram pattern were younger [(53.86±10.26) years old vs (67.20± 11.60) years old <0.01], at higher LDL-C level [3.54(2.88, 4.20) mmol/L vs 2.61(2.48, 2.73) mmol/L, =0.01], in lower classification degree of cardiac function [Killip I grade 12 cases (85.71%) vs 95 cases (43.98%), =0.04], and in shorter time between onset and the first electrocardiogram [171.77(47.56, 295.97) min vs 501.92(405.12, 598.72) min, =0.01]. Coronary angiography results indicated anterior descending or diagonal branch lesions.

Conclusions: The de Winter electrocardiogram pattern syndrome in patients with acute chest pain mostly indicates that the left anterior descending or the diagonal branch is subtotal or completely occluded, which is a special ST-segment elevation myocardial infarction equivalent and should attract the clinicians' extensive attention.
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http://dx.doi.org/10.11817/j.issn.1672-7347.2020.190276DOI Listing
December 2020

DGT, a novel heterocyclic diterpenoid, effectively suppresses psoriasis via inhibition of STAT3 phosphorylation.

Br J Pharmacol 2021 02 2;178(3):636-653. Epub 2020 Dec 2.

Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.

Background And Purpose: Psoriasis is a chronic immune-mediated inflammatory skin disease that easily recurs and is difficult to cure. DGT is a novel synthetic heterocyclic diterpenoid, whose structure has not been previously reported. We have investigated the action of DGT against psoriasis, specifically the hyperproliferation of epidermal keratinocytes, angiogenesis and pathogenic inflammatory responses.

Experimental Approach: We investigated its pharmacokinetics in skin after topical administration. We characterized its pharmacological actions in vitro and in vivo using cell proliferation assay, cell apoptosis assay, diethylstilbestrol-induced mouse vaginal epithelial cell mitosis model, tube formation assay, cell migration assay, chick embryonic chorioallantoic membrane (CAM) assay, histological, flow cytometric analysis and imiquimod (IMQ)-induced psoriasis-like model.

Key Results: DGT was found to be mainly distributed in the epidermis and dermis, which indicated that DGT was suitable as a topical treatment. DGT inhibited cell proliferation and induced apoptotic cell death of keratinocytes in vitro and in vivo. Moreover, DGT inhibited endothelial cell proliferation, tube formation and migration of in vitro angiogenesis, as well as in vivo CAM angiogenesis. In an IMQ-induced psoriasis-like skin inflammation murine model, topical application of DGT ameliorated keratinocyte proliferation and inflammatory response, especially in IL-17-related psoriasiform dermatitis. Furthermore, our results demonstrated that DGT prevented these pathological processes of psoriasis through suppression of STAT3 phosphorylation.

Conclusion And Implications: DGT has great potential as a novel therapeutic agent for the treatment of psoriatic skin disease.
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http://dx.doi.org/10.1111/bph.15306DOI Listing
February 2021

Left-Behind Status Worsens Prognosis of ST-Elevation Myocardial Infarction in Elderly Patients from Southwest China.

Med Sci Monit 2020 Oct 27;26:e927300. Epub 2020 Oct 27.

Department of Cardiology, Yongchuan Hospital of Chongqing Medical University, Chongqing, China (mainland).

BACKGROUND This study aimed to assess the association between left-behind status and the prognosis of ST-elevation myocardial infarction (STEMI). MATERIAL AND METHODS A total of 1 015 patients with STEMI patients from 4 tertiary medical centers in southwest China were enrolled and categorized into left-behind and not-left-behind groups. The primary endpoints were major adverse cardiovascular and cerebrovascular events (MACCEs), which were assessed with Kaplan-Meier curves. Multivariate Cox regression analyses were used to explore the predictive value of left-behind status for MACCEs. RESULTS Patients in the left-behind group were older than those in the not-left-behind group (70 vs. 65 years, P<0.001). The patients in the left-behind group had a lower incidence of history of coronary heart disease and diabetes mellitus than those in the not-left-behind group. Meanwhile, the left-behind group had higher levels of alanine aminotransferase (42 vs. 31, P<0.001), low-density lipoprotein cholesterol concentration (2.64 vs. 2.62, P=0.001) and cardiac troponin I (5.11 vs. 2.84, P=0.001) than the not-left-behind group. During the 18-month follow-up, the left-behind group experienced a higher rate of adverse events than the not-left-behind group (123/26.2% vs. 81/14.8%, P<0.001). After multivariate adjustment, the left-behind group also had a 1.778-fold (95% CI: 1.241-2.547, P=0.002) higher risk of experiencing MACCEs than the not-left-behind group. CONCLUSIONS Left-behind status is an independent predictor of STEMI prognosis.
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http://dx.doi.org/10.12659/MSM.927300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602365PMC
October 2020

Demonstrating a Continuous Set of Two-Qubit Gates for Near-Term Quantum Algorithms.

Phys Rev Lett 2020 Sep;125(12):120504

Google Research, Santa Barbara, California 93117, USA.

Quantum algorithms offer a dramatic speedup for computational problems in material science and chemistry. However, any near-term realizations of these algorithms will need to be optimized to fit within the finite resources offered by existing noisy hardware. Here, taking advantage of the adjustable coupling of gmon qubits, we demonstrate a continuous two-qubit gate set that can provide a threefold reduction in circuit depth as compared to a standard decomposition. We implement two gate families: an imaginary swap-like (iSWAP-like) gate to attain an arbitrary swap angle, θ, and a controlled-phase gate that generates an arbitrary conditional phase, ϕ. Using one of each of these gates, we can perform an arbitrary two-qubit gate within the excitation-preserving subspace allowing for a complete implementation of the so-called Fermionic simulation (fSim) gate set. We benchmark the fidelity of the iSWAP-like and controlled-phase gate families as well as 525 other fSim gates spread evenly across the entire fSim(θ,ϕ) parameter space, achieving a purity-limited average two-qubit Pauli error of 3.8×10^{-3} per fSim gate.
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http://dx.doi.org/10.1103/PhysRevLett.125.120504DOI Listing
September 2020

Protective effects of HY1702 on lipopolysaccharide-induced mild acute respiratory distress syndrome in mice.

Eur J Pharmacol 2020 Nov 16;887:173563. Epub 2020 Sep 16.

Shanghai University of Traditional Chinese Medicine, Shanghai, China. Electronic address:

Acute respiratory distress syndrome is an inflammatory disease with no effective pharmacological treatment. We investigated the therapeutic effect of HY1702, a new small molecule diterpene obtained from the processing and modification of Glaucocalyxin A and may exhibit anti-inflammatory activity. Specifically, we studied the anti-inflammatory effects of HY1702 on lipopolysaccharide-induced inflammatory responses in RAW264.7 and THP-1 cells in vitro and its protective efficacy on lipopolysaccharide-induced mild acute respiratory distress syndrome in mice. Our results showed that HY1702 significantly decreased lipopolysaccharide-induced inflammatory cytokine expression in RAW264.7 and THP-1 cells and attenuated the secretion of nitric oxide and prostaglandin E2 by down-regulating the expression of inducible nitric oxide synthase and cyclooxygenase 2 in RAW264.7 cells. In mice with lipopolysaccharide-induced mild acute respiratory distress syndrome, HY1702 alleviated histological alterations in the lungs and reduced the alveolar cavity protein leakage and inflammatory cytokine expression in murine bronchial alveolar lavage fluid. HY1702 decreased the myeloperoxidase activity and lung wet to dry weight ratio. In our mechanism studies in lipopolysaccharide-exposed RAW264.7 cells, HY1702 suppressed the inflammation stimulated by lipopolysaccharide through inhibiting phosphorylation of inhibitor of nuclear factor κB kinase subunit α/β (IKKα/β) and inhibitor of nuclear factor κB subunit α (IκBα), further affecting the nuclear transfer of phosphorylated p65. Meanwhile, phosphorylation of p38 mitogen-activated protein (MAP) kinase and extracellular signal-regulated kinase (ERK) was inhibited. These data suggest that HY1702 can reduce inflammation on lipopolysaccharide-stimulated macrophages and attenuate the symptoms of mild acute respiratory distress syndrome in a murine model by regulating the nuclear factor κB and MAP kinase signalling pathways.
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http://dx.doi.org/10.1016/j.ejphar.2020.173563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8368985PMC
November 2020

Structural Basis of Human Helicase DDX21 in RNA Binding, Unwinding, and Antiviral Signal Activation.

Adv Sci (Weinh) 2020 Jul 8;7(14):2000532. Epub 2020 Jun 8.

State Key Laboratory of Genetic Engineering Department of Neurology School of Life Sciences and Huashan Hospital Collaborative Innovation Center of Genetics and Development Engineering Research Center of Gene Technology of MOE Shanghai Engineering Research Center of Industrial Microorganisms Fudan University Shanghai 200438 China.

RNA helicase DDX21 plays vital roles in ribosomal RNA biogenesis, transcription, and the regulation of host innate immunity during virus infection. How DDX21 recognizes and unwinds RNA and how DDX21 interacts with virus remain poorly understood. Here, crystal structures of human DDX21 determined in three distinct states are reported, including the apo-state, the AMPPNP plus single-stranded RNA (ssRNA) bound pre-hydrolysis state, and the ADP-bound post-hydrolysis state, revealing an open to closed conformational change upon RNA binding and unwinding. The core of the RNA unwinding machinery of DDX21 includes one wedge helix, one sensor motif V and the DEVD box, which links the binding pockets of ATP and ssRNA. The mutant D339H/E340G dramatically increases RNA binding activity. Moreover, Hill coefficient analysis reveals that DDX21 unwinds double-stranded RNA (dsRNA) in a cooperative manner. Besides, the nonstructural (NS1) protein of influenza A inhibits the ATPase and unwinding activity of DDX21 via small RNAs, which cooperatively assemble with DDX21 and NS1. The structures illustrate the dynamic process of ATP hydrolysis and RNA unwinding for RNA helicases, and the RNA modulated interaction between NS1 and DDX21 generates a fresh perspective toward the virus-host interface. It would benefit in developing therapeutics to combat the influenza virus infection.
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http://dx.doi.org/10.1002/advs.202000532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375243PMC
July 2020

Orchestrating Opiate-Associated Memories in Thalamic Circuits.

Neuron 2020 09 16;107(6):1113-1123.e4. Epub 2020 Jul 16.

Neurosciences Graduate Program, Stanford University, Stanford, CA 94305, USA; Department of Biology, Stanford University, Stanford, CA 94305, USA. Electronic address:

Disrupting memories that associate environmental cues with drug experiences holds promise for treating addiction, yet accessing the distributed neural network that stores such memories is challenging. Here, we show that the paraventricular nucleus of the thalamus (PVT) orchestrates the acquisition and maintenance of opiate-associated memories via projections to the central nucleus of the amygdala (CeA) and nucleus accumbens (NAc). PVT→CeA activity associates morphine reward to the environment, whereas transient inhibition of the PVT→NAc pathway during retrieval causes enduring protection against opiate-primed relapse. Using brain-wide activity mapping, we revealed distributed network activities that are altered in non-relapsing mice, which enabled us to find that activating the downstream NAc→lateral hypothalamus (LH) pathway also prevents relapse. These findings establish the PVT as a key node in the opiate-associated memory network and demonstrate the potential of targeting the PVT→NAc→LH pathway for treating opioid addiction.
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http://dx.doi.org/10.1016/j.neuron.2020.06.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130576PMC
September 2020

Neutrophil to Lymphocyte Ratio Predicts Adverse Cardiovascular Outcome in Peritoneal Dialysis Patients Younger than 60 Years Old.

Mediators Inflamm 2020 20;2020:4634736. Epub 2020 May 20.

Department of Nephrology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.

Background: Neutrophil to lymphocyte ratio (NLR) is a new inflammatory marker; the relationship between NLR and adverse cardiovascular (CV) prognosis has been gradually emphasized in the general population. However, their association in peritoneal dialysis (PD) patients remains unclear.

Methods: From January 1, 2010, to May 31, 2017, a total of 1652 patients were recruited. NLR was categorized in triplicates: NLR ≤ 2.74, 2.74 < NLR ≤ 3.96, and NLR > 3.96. Kaplan-Meier cumulative incidence curve and multivariable COX regression analysis were used to determine the relationship between NLR and the incidence of adverse CV outcome, while a competitive risk model was applied to assess the effects of other outcomes on adverse CV prognosis. Besides, forest plot was investigated to analyze the adverse CV prognosis in different subgroups.

Results: During follow-up, 213 new-onset CV events and 153 CV disease (CVD) deaths were recorded. Multivariable COX regression models showed that the highest tertile of NLR level was associated with increased risk of CV events (HR = 1.39, 95%CI = 1.01-1.93, = 0.046) and CVD mortality (HR = 1.81, 95%CI = 1.22-2.69, = 0.003), while compared to the lowest tertile. Competitive risk models showed that the differences in CV event ( < 0.001) and CVD mortality ( = 0.004) among different NLR groups were still significant while excluding the effects of other outcomes. In subgroups, with each 1 increased in the NLR level, adjusted HR of new-onset CV event was 2.02 (95%CI = 1.26 - 3.23, = 0.003) and CVD mortality was 2.98 (95%CI = 1.58 - 5.62, = 0.001) in the younger group (age < 60 years).

Conclusions: NLR is an independent risk factor for adverse CV prognosis in PD patients younger than 60 years old.
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http://dx.doi.org/10.1155/2020/4634736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256716PMC
July 2021

Structure-guided protein engineering increases enzymatic activities of the SGNH family esterases.

Biotechnol Biofuels 2020 15;13:107. Epub 2020 Jun 15.

Key Laboratory of Marine Ecosystem Dynamics, Ministry of Natural Resources, Ministry of Natural Resources & Second Institute of Oceanography, Hangzhou, 310012 China.

Background: Esterases and lipases hydrolyze short-chain esters and long-chain triglycerides, respectively, and therefore play essential roles in the synthesis and decomposition of ester bonds in the pharmaceutical and food industries. Many SGNH family esterases share high similarity in sequences. However, they have distinct enzymatic activities toward the same substrates. Due to a lack of structural information, the detailed catalytic mechanisms of these esterases remain barely investigated.

Results: In this study, we identified two SGNH family esterases, CrmE10 and AlinE4, from marine bacteria with significantly different preferences for pH, temperature, metal ion, and organic solvent tolerance despite high sequence similarity. The crystal structures of these two esterases, including wild type and mutants, were determined to high resolutions ranging from 1.18 Å to 2.24 Å. Both CrmE10 and AlinE4 were composed of five β-strands and nine α-helices, which formed one compact N-terminal α/β globular domain and one extended C-terminal domain. The aspartic residues (D178 in CrmE10/D162 in AlinE4) destabilized the conformations of the catalytic triad (Ser-Asp-His) in both esterases, and the metal ion Cd might reduce enzymatic activity by blocking proton transfer or substrate binding. CrmE10 and AlinE4 showed distinctly different electrostatic surface potentials, despite the similar atomic architectures and a similar swap catalytic mechanism. When five negatively charged residues (Asp or Glu) were mutated to residue Lys, CrmE10 obtained elevated alkaline adaptability and significantly increased the enzymatic activity from 0 to 20% at pH 10.5. Also, CrmE10 mutants exhibited dramatic change for enzymatic properties when compared with the wide-type enzyme.

Conclusions: These findings offer a perspective for understanding the catalytic mechanism of different esterases and might facilitate the industrial biocatalytic applications.
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http://dx.doi.org/10.1186/s13068-020-01742-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294632PMC
June 2020

Cathelicidin-DM is an Antimicrobial Peptide from and Has Wound-Healing Therapeutic Potential.

ACS Omega 2020 Apr 14;5(16):9301-9310. Epub 2020 Apr 14.

Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan 650500, China.

Antimicrobial peptides (AMPs) are a class of templates with application potential for drug development. Amphibians are important sources of AMPs. is the main source of traditional Chinese medicine "Chansu", which has anti-infection effect while without a clear mechanism. This study aimed to find the cathelicidin peptide in and then investigate the activity and , and an AMP-encoding gene (cathelicidin-DM, GenBank: KJ820824.1) was obtained from the constructed cDNA library of . The MIC test and SYTOX Green uptake were used for the evaluation of the bactericidal capacity and mechanisms. The serum stability tests were used for the evaluation of the application potential. The skin wound infection model and imaging were used for application of possibility evaluation. The results showed that cathelicidin-DM was a 37 amino acid AMP with good bactericidal ability, which was similar to melittin: both can kill bacteria within 15 min. Moreover, cathelicidin-DM exhibits good therapeutic potential in the mouse wound infection model, and it can be enriched to the site of infection for treatment. Thus, cathelicidin-DM could be a new template for antimicrobial drug development given its good antibacterial activity and .
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http://dx.doi.org/10.1021/acsomega.0c00189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191562PMC
April 2020

Syntheses and Preliminary Evaluation of Dual Target PET Probe [18F]-NOTA-Gly3- E (2PEG4-RGD-WH701) for PET Imaging of Breast Cancer.

Anticancer Agents Med Chem 2020 ;20(13):1548-1557

Department of Nuclear Medicine & Minnan PET Center, Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, Teaching Hospital of Fujian Medical University, Xiamen, China.

Purpose: Tumor Necrosis Factor Receptor 1 (TNFR1) and integrin αvβ3 receptor are overexpressed in breast cancer. We hypothesized that a peptide ligand recognizing both receptors in a single receptor-binding probe would be advantageous. Here, we developed a novel 18F-labeled fusion peptide probe [18F]-NOTA-Gly3- E(2PEG4-RGD-WH701) targeting dual receptors (TNFR1 and αvβ3) and evaluated the diagnostic efficacy of this radioactive probe in both MDA-MB-231 and MCF-7 xenograft models in mice.

Methods: The NOTA-conjugated RGD-WH701 analog was radiolabeled with 18F using NOTA-AlF chelation method. We used two PEG4 molecules and Glutamic acid (Glu) to covalently link c(RGDyK) with WH701. Gly3 was also added to further improve the water solubility and pharmacokinetic properties of the probe. The expression of TNFR1 and Integrin αvβ3 in MCF-7 and MDA-MB-231 cells was detected by western blot analysis and immunofluorescence staining. The tumor-targeting characteristics of [18F]-NOTA-Gly3-E(2PEG4-RGDWH701) were assessed in nude mice bearing MDA-MB-231 and MCF-7 xenografts.

Results: HPLC analysis of the product NOTA-G3-E (2P4-RGD-WH701) revealed a purity >95%. The yield after attenuation correction was approximately 33.5%±2.8% (n=5), and the radiochemical purity was above 95%. The MDA-MB-231 tumor uptake of [18F]-NOTA-Gly3-E(2PEG4-RGD-WH701) was 1.14±0.14%ID/g, as measured by PET at 40min postinjection (p.i.). In comparison, the tumor uptake of [18F]-NOTA-RGD and [18F]- NOTA-WH701 in MDA-MB-231 xenografts was 0.96±0.13%ID/g and 0.93±0.28%ID/g, respectively. The MCF-7 tumor uptake of [18F]-NOTA-Gly3-E(2PEG4-RGD-WH701) was 1.22±0.11%ID/g, as measured by PET at 40min postinjection (p.i.). In comparison, the tumor uptake of [18F]-NOTA-RGD and [18F]-NOTA-WH701 in MCF-7 xenografts was 0.99±0.18%ID/g and 0.57±0.08%ID/g, respectively.

Conclusion: [18F]AlF-NOTA-Gly3-E(2PEG4-RGD-WH701) was successfully synthesized and labeled with 18F. The results from the microPET/CT and biodistribution studies of [18F]AlF-NOTA-Gly3-E(2PEG4-RGDWH701) showed that the tracer could specifically target TNFR1 and integrin αvβ3 receptors.
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http://dx.doi.org/10.2174/1871520620666200424101936DOI Listing
June 2021

Nervous system involvement after infection with COVID-19 and other coronaviruses.

Brain Behav Immun 2020 07 30;87:18-22. Epub 2020 Mar 30.

Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China. Electronic address:

Viral infections have detrimental impacts on neurological functions, and even to cause severe neurological damage. Very recently, coronaviruses (CoV), especially severe acute respiratory syndrome CoV 2 (SARS-CoV-2), exhibit neurotropic properties and may also cause neurological diseases. It is reported that CoV can be found in the brain or cerebrospinal fluid. The pathobiology of these neuroinvasive viruses is still incompletely known, and it is therefore important to explore the impact of CoV infections on the nervous system. Here, we review the research into neurological complications in CoV infections and the possible mechanisms of damage to the nervous system.
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http://dx.doi.org/10.1016/j.bbi.2020.03.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146689PMC
July 2020

Crystal structure of human archease, a key cofactor of tRNA splicing ligase complex.

Int J Biochem Cell Biol 2020 05 29;122:105744. Epub 2020 Mar 29.

State Key Laboratory of Genetic Engineering, Department of Neurology, School of Life Sciences and Huashan Hospital, Fudan University, Shanghai, 200438, China. Electronic address:

The human archease, hereafter named HArch, is identified as a key cofactor of the tRNA-splicing ligase complex, and a potential therapeutic target for treating nervous system injuries. However, little is known about the structural basis of HArch in tRNA maturation, mRNA splicing, and RNA repair. Here we report the crystal structures of HArch and its two mutants D51A and D178A with resolutions ranging from 1.96 Å to 3.4 Å. HArch is composed of an extended N-terminal protrusion domain (NTD) and one compacted C-terminal domain (CTD). Unlike previously reported homologous proteins, the NTD of the first subunit interacts with the CTD of the second one, and this interaction might be important for maintaining protein stability. Moreover, HArch interacts and colocalizes with RNA ligase RTCB in cells. Our current study reveals the atomic structure of HArch and may help us understand its function in mRNA splicing.
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http://dx.doi.org/10.1016/j.biocel.2020.105744DOI Listing
May 2020

The cholinergic anti-inflammatory pathway could be an important mechanism underling the comorbidity of depression and cardiovascular disease: A comment to Shao et al.

Psychiatry Res 2020 Feb 19;286:112881. Epub 2020 Feb 19.

Department of Cardiology, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China. Electronic address:

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http://dx.doi.org/10.1016/j.psychres.2020.112881DOI Listing
February 2020
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