Publications by authors named "Ziheng Zhang"

46 Publications

A New Method for Studying RNA-binding Proteins on Specific RNAs.

Bio Protoc 2021 May 20;11(10):e4022. Epub 2021 May 20.

School of Life Science and Technology, ShanghaiTech University, Shanghai, China.

Proximity-based protein labeling has been developed to identify protein-nucleic acid interactions. We have reported a novel method termed CRUIS (CRISPR-based RNA-United Interacting System), which captures RNA-protein interactions in living cells by combining the RNA-binding capacity of CRISPR/Cas13 and the proximity-tagging activity of PUP-IT. Enzymatically deactivated Cas13a (dCas13a) is fused to the proximity labeling enzyme PafA. In the presence of a guide RNA, dCas13a binds specific target RNA region, while the fused PafA mediates the labeling of biotin-tagged Pup on proximal proteins. The labeled proteins can be enriched by streptavidin pull-down and identified by mass spectrometry. Here we describe the general procedure for capturing RNA-protein interactions using this method.
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http://dx.doi.org/10.21769/BioProtoc.4022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187123PMC
May 2021

Simple and precise characterization of differential modal group delay arising in few-mode fiber.

Opt Lett 2021 Jun;46(12):2856-2859

In this Letter, we propose a simple and high-precision differential modal group delay (DMGD) characterization method for few-mode fibers (FMF) by using the frequency-modulated continuous wave. Since the detected signals are located at the low-frequency range, our DMGD characterization method waives the use of expensive equipment, such as vector network or optical spectrum analyzers. Due to the high linearity of the used Mach-Zehnder modulator, our DMGD measurement is free from the complex auxiliary interferometer, leading to an improvement of characterization precision. Meanwhile, we propose a novel spectrum recovery algorithm to overcome the shortcoming that the traditional fast Fourier transform (FFT) method is incapable to deal with spectrum features arising in a periodic signal. Therefore, the characterization precision is no longer limited by the FFT length. When a commercial 23299.8 m two-mode fiber is used in the experiment, the DMGD measurement of mode relative to mode has a high precision of ±0.007/ over the C-band. Our proposed method shows the potential for characterizing the wavelength-dependent DMGD of FMF with more than two LP modes.
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http://dx.doi.org/10.1364/OL.423950DOI Listing
June 2021

Gut microbiota mediates the effects of curcumin on enhancing Ucp1-dependent thermogenesis and improving high-fat diet-induced obesity.

Food Funct 2021 Jun 7. Epub 2021 Jun 7.

Jilin Collaborative Innovation Center for Antibody Engineering, Jilin Medical University, Jilin, Jilin, China.

Due to extremely poor systemic bioavailability, the mechanism by which curcumin increases energy expenditure remains unelucidated. Accumulating evidence suggests a strong association between the gut microbiota (GM) and energy metabolism. We investigated whether the GM mediates the effects of curcumin on improving energy homeostasis. High-fat diet (HFD)-fed wild type, uncoupling protein 1 (Ucp1) knockout and G protein-coupled membrane receptor 5 (TGR5) knockout mice were treated with curcumin (100 mg kg-1 d-1, p.o.). Curcumin-treated HFD-fed mice displayed decreased body weight gain and augmented cold tolerance due to enhanced adaptive thermogenesis as compared with that in control mice. The anti-obesity effects of curcumin were abolished by Ucp1 knockout. 16S ribosomal DNA sequencing analysis revealed that curcumin restructured the GM in HFD-fed mice. Fecal microbiota transplantation (FMT) and endogenous GM depletion indicated that the GM mediated the enhanced effect of curcumin on Ucp1-dependent thermogenesis. Curcumin altered bile acid (BA) metabolism with increased fractions of circulating deoxycholic acid (DCA) and lithocholic acid (LCA), which are the two most potent ligands for TGR5. Consistently, the enhanced effect of curcumin on Ucp1-dependent thermogenesis was eliminated by TGR5 knockout. Curcumin requires the GM and TGR5 to activate the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway in thermogenic adipose tissue. Here, we demonstrated that the GM mediates the effects of curcumin on enhancing Ucp1-dependent thermogenesis and ameliorating HFD-induced obesity by influencing BA metabolism. We disclosed the potential of nutritional and pharmacologic manipulations of the GM to enhance Ucp1-dependent thermogenesis in the prevention and treatment of obesity.
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http://dx.doi.org/10.1039/d1fo00671aDOI Listing
June 2021

Design, synthesis, and biological evaluation of 5-aminotetrahydroquinoline-based LSD1 inhibitors acting on Asp375.

Arch Pharm (Weinheim) 2021 May 13:e2100102. Epub 2021 May 13.

Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China.

The abnormal expression of lysine-specific histone demethylase 1 (LSD1) is associated with different cancer types, and LSD1 inhibitory activity seems to have high therapeutic potential in cancer treatment. Here, we report the design, synthesis, and biochemical evaluation of novel 5-aminotetrahydroquinoline-based LSD1 inhibitors. Among them, compounds A6, A8, B1-B5, and C4 showed preferable inhibitory effects on LSD1, with IC  = 0.19-0.82 µM. Several potent compounds were selected to evaluate their antiproliferative activity on A549 cells and MCF-7 cells with a high expression of LSD1. The potential binding modes of the compounds were revealed through molecular docking to rationalize the potency of compounds toward LSD1. Our data recognized that the 5-aminotetrahydroquinoline scaffold may serve as a starting point for developing potent LSD1 inhibitors for cancer therapy.
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http://dx.doi.org/10.1002/ardp.202100102DOI Listing
May 2021

Design, synthesis and biological evaluation of novel benzofuran derivatives as potent LSD1 inhibitors.

Eur J Med Chem 2021 Aug 24;220:113501. Epub 2021 Apr 24.

Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, China.

Lysine-specific demethylase 1 (LSD1) is a FAD-dependent enzyme, which has been proposed as a promising target for therapeutic cancer. Herein, a series of benzofuran derivatives were designed, synthesized and biochemical evaluated as novel LSD1 inhibitors based on scaffold hopping and conformational restriction strategy. Most of the compounds potently suppressed the enzymatic activities of LSD1 and potently inhibited tumor cells proliferation. In particular, the representative compound 17i exhibited excellent LSD1 inhibition at the molecular levels with IC = 0.065 μM, as well as anti-proliferation against MCF-7, MGC-803, H460, A549 and THP-1 tumor cells with IC values of 2.90 ± 0.32, 5.85 ± 0.35, 2.06 ± 0.27, 5.74 ± 1.03 and 6.15 ± 0.49 μM, respectively. The binding modes of these compounds were rationalized by molecular docking. Meanwhile, a preliminary druggability evaluation showed that compound 17i displayed favorable liver microsomal stability and weak inhibitory activity against CYPs at 10 μM. Remarkably, H460 xenograft tumors studies revealed that 17i demonstrated robust in vivo antitumor efficacy without significant side effects. All the results demonstrated that compound 17i could represent a promising lead for further development.
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http://dx.doi.org/10.1016/j.ejmech.2021.113501DOI Listing
August 2021

Effects of a School-Based Physical Activity Intervention for Obesity and Health-Related Physical Fitness in Adolescents With Intellectual Disability: Protocol for a Randomized Controlled Trial.

JMIR Res Protoc 2021 Mar 22;10(3):e25838. Epub 2021 Mar 22.

Department of Sport, Physical Education and Health, Hong Kong Baptist University, Hong Kong, China.

Background: Childhood obesity accompanied by lower levels of health-related physical fitness (HRPF) is a major threat to public health both internationally and locally. Children with intellectual disability, especially adolescents, have a higher risk of being overweight/obese and having poor HRPF levels. Therefore, more interventions are needed to help this population attain their optimal health levels. However, there has been relatively limited research on this population compared with on their typically developing peers.

Objective: The proposed study aims to fill this knowledge gap by developing and examining the success of a physical activity (PA) intervention for the target population.

Methods: The proposed study will be a 12-week, school-based randomized controlled trial. The participants (N=48) will be recruited from special schools for students with mild intellectual disability and then randomly allocated to either the intervention group (IG) or the wait-list control group (CG). During the intervention period, the participants in the IG will receive a fun game-based moderate-to-vigorous PA (MVPA) training program (2 sessions/week, 60 minutes/session, for a total of 24 sessions). The intensity of the activities will increase in a progressive manner. Participants in the CG will receive no program during the study period, but the same PA program will be provided to them after the completion of the study. To observe and evaluate the sustaining effects of the intervention, follow-up testing will be scheduled for the participants 12 weeks after the intervention concludes. The study outcomes will include primary outcomes (obesity- and fitness-related outcomes) and a secondary outcome (blood pressure). All of the measurements will be taken at 3 time points. After the follow-up tests, the same PA training program will be provided to the participants in the CG.

Results: This study is ongoing. The participants were recruited from October 2020 to November 2020. The total duration of the study is 13 months. Study results are expected at the end of 2021.

Conclusions: The proposed study is expected to reduce obesity and improve HRPF levels in children with intellectual disability. If proven effective, the intervention will be made accessible to more special schools and mainstream schools with students with intellectual disability. Furthermore, the study can serve as an example for international researchers, policy makers, and members of the public who are seeking to tackle the problem of obesity and poor HRPF among children with intellectual disability.

Trial Registration: ClinicalTrials.gov NCT04554355; https://www.clinicaltrials.gov/ct2/show/NCT04554355.

International Registered Report Identifier (irrid): PRR1-10.2196/25838.
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http://dx.doi.org/10.2196/25838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088867PMC
March 2021

Malonate Promotes Adult Cardiomyocyte Proliferation and Heart Regeneration.

Circulation 2021 May 5;143(20):1973-1986. Epub 2021 Mar 5.

Department of Cell and Regenerative Biology (J.B., R.J.S., E.B.B., W.G.P., Z.Z., A.I.M.), University of Wisconsin-Madison School of Medicine and Public Health.

Background: Neonatal mouse cardiomyocytes undergo a metabolic switch from glycolysis to oxidative phosphorylation, which results in a significant increase in reactive oxygen species production that induces DNA damage. These cellular changes contribute to cardiomyocyte cell cycle exit and loss of the capacity for cardiac regeneration. The mechanisms that regulate this metabolic switch and the increase in reactive oxygen species production have been relatively unexplored. Current evidence suggests that elevated reactive oxygen species production in ischemic tissues occurs as a result of accumulation of the mitochondrial metabolite succinate during ischemia via succinate dehydrogenase (SDH), and this succinate is rapidly oxidized at reperfusion. Mutations in SDH in familial cancer syndromes have been demonstrated to promote a metabolic shift into glycolytic metabolism, suggesting a potential role for SDH in regulating cellular metabolism. Whether succinate and SDH regulate cardiomyocyte cell cycle activity and the cardiac metabolic state remains unclear.

Methods: Here, we investigated the role of succinate and SDH inhibition in regulation of postnatal cardiomyocyte cell cycle activity and heart regeneration.

Results: Our results demonstrate that injection of succinate into neonatal mice results in inhibition of cardiomyocyte proliferation and regeneration. Our evidence also shows that inhibition of SDH by malonate treatment after birth extends the window of cardiomyocyte proliferation and regeneration in juvenile mice. Remarkably, extending malonate treatment to the adult mouse heart after myocardial infarction injury results in a robust regenerative response within 4 weeks after injury via promoting adult cardiomyocyte proliferation and revascularization. Our metabolite analysis after SDH inhibition by malonate induces dynamic changes in adult cardiac metabolism.

Conclusions: Inhibition of SDH by malonate promotes adult cardiomyocyte proliferation, revascularization, and heart regeneration via metabolic reprogramming. These findings support a potentially important new therapeutic approach for human heart failure.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.049952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131241PMC
May 2021

Application of acellular dermal matrix to reconstruct the defects after hypopharyngeal carcinoma resection.

Am J Otolaryngol 2021 Mar-Apr;42(2):102847. Epub 2020 Dec 17.

Department of Otorhinolaryngology, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang, China. Electronic address:

Purpose: Reconstruction of the defects and recovery of the laryngopharyngeal function after resection of hypopharyngeal carcinoma are crucial for patients to promote the rate of survival and the quality of life. We launched this study to explore the advantages and limitations of acellular dermal matrix applied in the reconstruction of the defects after hypopharyngeal carcinoma surgery.

Materials And Methods: Collected the clinical and pathological data of patients with hypopharyngeal carcinoma, divided them into 2 groups according to the repair materials used (pectoralis major myocutaneous flap or acellular dermal matrix). The clinical data and postoperative complications were analyzed and compared.

Results: No matter whether the pectoralis major myocutaneous flap or acellular dermal matrix was used to repair hypopharyngeal cancer resection defects, the postoperative complications, especially the pharyngeal fistula rate, were not significantly different. The postoperative drainage volume of patients with acellular dermal matrix was less than that of patients with pectoralis major myocutaneous flap.

Conclusions: Acellular dermal matrix is a safe and effective biomedical material for hypopharyngeal cancer operation defects repair and pharyngeal function reconstruction, which can simplify the operation process, reduce the postoperative drainage volume, and decrease the risk of wound infection or pharyngeal fistula.
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http://dx.doi.org/10.1016/j.amjoto.2020.102847DOI Listing
December 2020

Forecasting the long-term trend of COVID-19 epidemic using a dynamic model.

Sci Rep 2020 12 3;10(1):21122. Epub 2020 Dec 3.

Jarvis Lab, Department of Medicine and Healthcare, Tencent Technology (Shenzhen) Company, Shenzhen, 518000, China.

The current outbreak of coronavirus disease 2019 (COVID-19) has recently been declared as a pandemic and spread over 200 countries and territories. Forecasting the long-term trend of the COVID-19 epidemic can help health authorities determine the transmission characteristics of the virus and take appropriate prevention and control strategies beforehand. Previous studies that solely applied traditional epidemic models or machine learning models were subject to underfitting or overfitting problems. We propose a new model named Dynamic-Susceptible-Exposed-Infective-Quarantined (D-SEIQ), by making appropriate modifications of the Susceptible-Exposed-Infective-Recovered (SEIR) model and integrating machine learning based parameter optimization under epidemiological rational constraints. We used the model to predict the long-term reported cumulative numbers of COVID-19 cases in China from January 27, 2020. We evaluated our model on officially reported confirmed cases from three different regions in China, and the results proved the effectiveness of our model in terms of simulating and predicting the trend of the COVID-19 outbreak. In China-Excluding-Hubei area within 7 days after the first public report, our model successfully and accurately predicted the long trend up to 40 days and the exact date of the outbreak peak. The predicted cumulative number (12,506) by March 10, 2020, was only 3·8% different from the actual number (13,005). The parameters obtained by our model proved the effectiveness of prevention and intervention strategies on epidemic control in China. The prediction results for five other countries suggested the external validity of our model. The integrated approach of epidemic and machine learning models could accurately forecast the long-term trend of the COVID-19 outbreak. The model parameters also provided insights into the analysis of COVID-19 transmission and the effectiveness of interventions in China.
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http://dx.doi.org/10.1038/s41598-020-78084-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713358PMC
December 2020

Impact of prior cancer history on the survival of patients with larynx cancer.

BMC Cancer 2020 Nov 23;20(1):1137. Epub 2020 Nov 23.

Department of otolaryngology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, 325000, P. R. China.

Background: Patients with a prior history of cancer are commonly excluded from clinical trial. Increasing number of studies implied that a prior cancer did not adversely affect the clinical outcome among various types of cancer patients. However, the impact of prior cancer on survival of larynx cancer patients remains largely unknown. The aim of this study was to evaluate the prevalence of prior cancer and assess its impact on survival of patients diagnosed with larynx cancer.

Methods: Patients with larynx cancer as the first or second primary malignancy diagnosed from 2004 to 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) was conducted to balance baseline characteristics. Kaplan-Meier method, multivariate Cox proportional hazard model, and multivariate competing risk model were performed for survival analysis.

Results: A total of 24,812 eligible patients with larynx cancer were included in the study, wherein a total of 2436 patients (9.8%) had a prior history of cancer. Prostate (36%), lung and bronchus (10%), urinary bladder (7%), and breast (6%) were the most common types of prior cancer. A prior cancer history served as a risk factor for overall survival (AHR =1.30; 95% CI [1.21-1.41]; P < 0.001) but a protective factor for cancer-specific mortality (AHR = 0.83; 95% CI [0.72-0.94]; P = 0.004) in comparison with those without prior cancer. The subgroup analysis showed that a prior history of cancer adversely affected overall survival of patients with larynx cancer in most subgroups stratified by timing and types of prior cancer, as well as by different clinicopathologic features.

Conclusion: Our study indicated an adverse survival impact of a prior history of cancer on patients with larynx cancer. Except for a few particular prior cancer, clinical trials should be considered prudently for laryngeal cancer patients with prior cancers.
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http://dx.doi.org/10.1186/s12885-020-07634-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685658PMC
November 2020

Mechanistic Study of Synergistic Antimicrobial Effects between Poly (3-hydroxybutyrate) Oligomer and Polyethylene Glycol.

Polymers (Basel) 2020 Nov 18;12(11). Epub 2020 Nov 18.

Research Center for Smart Wearable Technology, Institute of Textiles and Clothing, The Hong Kong Polytechnic University, Hong Kong 999077, China.

Extended from our previous finding that poly (3-hydroxybutyrate) (PHB) oligomer is an effective antimicrobial agent against gram-positive bacteria, gram-negative bacteria, fungi and multi-drug resistant bacteria, this work investigates the effect of polyethylene glycol (PEG) on the antimicrobial effect of PHB oligomer. To investigate and explain this promoting phenomenon, three hypothetic mechanisms were proposed, that is, generation of new antimicrobial components, degradation of PHB macromolecules and dissolution/dispersion of PHB oligomer by PEG. With a series of systematic experiments and characterizations of high-performance liquid chromatography-mass spectrometry (HPLC-MS), it was deducted that PEG promotes the antimicrobial effect of PHB oligomer synergistically through dissolution/dispersion, owing to its amphipathy, which improves the hydrophilicity of PHB oligomer.
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http://dx.doi.org/10.3390/polym12112735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698724PMC
November 2020

Descending Necrotizing Mediastinitis: Analysis of 9 Cases in Our Hospital.

Ear Nose Throat J 2020 Jul 5:145561320933964. Epub 2020 Jul 5.

Department of Otolaryngology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.

Objectives: Descending necrotizing mediastinitis (DNM) is a serious and progressive infection involving the neck and chest and with high mortality if not treated quickly and properly. The aim of this study is to share our practices for managing this condition.

Methods: We retrospectively evaluated 9 patients diagnosed with DNM in our hospital between January 2006 and October 2019. Age, gender, origin of infection, length of hospital stay, microorganisms present, type of surgical treatment, and clinical outcomes were reviewed.

Results: All patients underwent surgery to drain neck and mediastinal secretions and collections. Three (33.3%) patients were treated with transcervical drainage alone, and 6 (66.7%) patients were treated with combined transcervical and transthoracic drainage. Reoperations were reported in 3 (33.3%) cases. The average length of hospital stay was 22.78 ± 10.05 days (range: 9-40 days). The average length of intensive care unit stay was 6.44 ± 10.10 days (range: 0-25 days). There were no in-hospital deaths, and all patients were discharged home with good outcomes.

Conclusions: To improve the prognosis of DNM, we suggest early and adequate debridement of all affected areas along with the proper use of antibiotics. A multidisciplinary approach involving both cardiothoracic and ENT surgeons is also required.
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http://dx.doi.org/10.1177/0145561320933964DOI Listing
July 2020

Tsinghua facial expression database - A database of facial expressions in Chinese young and older women and men: Development and validation.

PLoS One 2020 15;15(4):e0231304. Epub 2020 Apr 15.

Department of Psychology, School of Social Sciences, Tsinghua University, Beijing, China.

Perception of facial identity and emotional expressions is fundamental to social interactions. Recently, interest in age associated changes in the processing of faces has grown rapidly. Due to the lack of older faces stimuli, most previous age-comparative studies only used young faces stimuli, which might cause own-age advantage. None of the existing Eastern face stimuli databases contain face images of different age groups (e.g. older adult faces). In this study, a database that comprises images of 110 Chinese young and older adults displaying eight facial emotional expressions (Neutral, Happiness, Anger, Disgust, Surprise, Fear, Content, and Sadness) was constructed. To validate this database, each image was rated on the basis of perceived facial expressions, perceived emotional intensity, and perceived age by two different age groups. Results have shown an overall 79.08% correct identification rate in the validation. Access to the freely available database can be requested by emailing the corresponding authors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231304PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7159817PMC
July 2020

Capturing the Cardiac Injury Response of Targeted Cell Populations via Cleared Heart Three-Dimensional Imaging.

J Vis Exp 2020 03 17(157). Epub 2020 Mar 17.

Department of Cell and Regenerative Biology, University of Wisconsin-Madison School of Medicine and Public Health;

Cardiovascular disease outranks all other causes of death and is responsible for a staggering 31% of mortalities worldwide. This disease manifests in cardiac injury, primarily in the form of an acute myocardial infarction. With little resilience following injury, the once healthy cardiac tissue will be replaced by fibrous, non-contractile scar tissue and often be a prelude to heart failure. To identify novel treatment options in regenerative medicine, research has focused on vertebrates with innate regenerative capabilities. One such model organism is the neonatal mouse, which responds to cardiac injury with robust myocardial regeneration. In order to induce an injury in the neonatal mouse that is clinically relevant, we have developed a surgery to occlude the left anterior descending artery (LAD), mirroring a myocardial infarction triggered by atherosclerosis in the human heart. When matched with the technology to track changes both within cardiomyocytes and non-myocyte populations, this model provides us with a platform to identify the mechanisms that guide heart regeneration. Gaining insight into changes in cardiac cell populations following injury once relied heavily on methods such as tissue sectioning and histological examination, which are limited to two-dimensional analysis and often damage the tissue in the process. Moreover, these methods lack the ability to trace changes in cell lineages, instead providing merely a snapshot of the injury response. Here, we describe how technologically advanced methods in lineage tracing models, whole organ clearing, and three-dimensional (3D) whole-mount microscopy can be used to elucidate mechanisms of cardiac repair. With our protocol for neonatal mouse myocardial infarction surgery, tissue clearing, and 3D whole organ imaging, the complex pathways that induce cardiomyocyte proliferation can be unraveled, revealing novel therapeutic targets for cardiac regeneration.
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http://dx.doi.org/10.3791/60482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530371PMC
March 2020

Capturing RNA-protein interaction via CRUIS.

Nucleic Acids Res 2020 05;48(9):e52

School of Life Science and Technology, ShanghaiTech University, Shanghai, China.

No RNA is completely naked from birth to death. RNAs function with and are regulated by a range of proteins that bind to them. Therefore, the development of innovative methods for studying RNA-protein interactions is very important. Here, we developed a new tool, the CRISPR-based RNA-United Interacting System (CRUIS), which captures RNA-protein interactions in living cells by combining the power of CRISPR and PUP-IT, a novel proximity targeting system. In CRUIS, dCas13a is used as a tracker to target specific RNAs, while proximity enzyme PafA is fused to dCas13a to label the surrounding RNA-binding proteins, which are then identified by mass spectrometry. To identify the efficiency of CRUIS, we employed NORAD (Noncoding RNA activated by DNA damage) as a target, and the results show that a similar interactome profile of NORAD can be obtained as by using CLIP (crosslinking and immunoprecipitation)-based methods. Importantly, several novel NORAD RNA-binding proteins were also identified by CRUIS. The use of CRUIS facilitates the study of RNA-protein interactions in their natural environment, and provides new insights into RNA biology.
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http://dx.doi.org/10.1093/nar/gkaa143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229851PMC
May 2020

The loss of dopaminergic neurons in DEC1 deficient mice potentially involves the decrease of PI3K/Akt/GSK3β signaling.

Aging (Albany NY) 2019 12 28;11(24):12733-12753. Epub 2019 Dec 28.

Department of Pharmacology, Nanjing Medical University, Nanjing, China.

Here we study the effects of differentiated embryonic chondrocyte gene 1(DEC1) deficiency on midbrain dopaminergic(DA) neurons in the substantia nigra pars compacta(SNpc) through behavioral, histological and molecular analysis. We have found that compared to the age-matched WT mice, DEC1 deficient mice show a decrease in locomotor activity and motor coordination, which shows the main features of Parkinson's disease(PD). But there is no significant difference in spatial learning and memory skills between WT and DEC1 KO mice. Compared to the age-matched WT mice, DEC1 deficient mice exhibit the loss of DA neurons in the SNpc and reduction of dopamine and its metabolites in the striatum. The activated caspase-3 and TH/TUNEL cells increase in the SNpc of 6- and 12-month-old DEC1 KO mice compared to those of the age-matched WT mice. But we haven't found any NeuN/TUNEL cell increase in the hippocampus of the above two types of mice at the age of 6 months. Furthermore, DEC1 deficiency leads to a significant inhibition of PI3K/Akt/GSK3β signaling pathway. Additionally, LiCl could rescue the DA neuron loss of midbrain in the 6-month-old DEC1 KO mice. Taken together, the loss of DA neurons in the DEC1 deficient mice potentially involves the downregulation of PI3K/Akt/GSK3β signaling.
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http://dx.doi.org/10.18632/aging.102599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949058PMC
December 2019

Curcumin analog, WZ37, promotes G2/M arrest and apoptosis of HNSCC cells through Akt/mTOR inhibition.

Toxicol In Vitro 2020 Jun 18;65:104754. Epub 2019 Dec 18.

Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address:

Head and neck squamous cell carcinoma (HNSCC) is a leading form of malignancy arising from the head and neck region. Existing conventional therapies are toxic and induce resistance to advanced HNSCC, therefore, new highly efficient therapeutic agents are urgently needed. The present study investigated the anti-cancer efficacy of WZ37, a curcumin analog, in HNSCC cell lines, and defined the mechanism of this activity. Results indicated that WZ37 inhibited proliferation of several HNSCC cell types by G2/M cycle arrest, promoted expression of a pro-apoptotic protein profile, and induced ROS-dependent mitochondrial injury and ER stress. Pre-treatment with NAC, an ROS scavenger, lowered the anti-cancer activity of WZ37 in HEP-2 cells. Long-term treatment of WZ37 (24 h) decreased Akt/mTOR phosphorylation which was accompanied by increased expression of BAD and PTEN. Moreover, co-treatment of WZ37 with MK-2206 (Akt inhibitor) promoted cancer cell apoptosis. Our findings indicated that the anti-cancer potential of WZ37 was attributed to ROS-dependent cell cycle arrest, mitochondrial injury, and ER stress, leading to apoptosis. The basis of the HNSCC cell apoptosis was through a mechanism of inhibition of the oxidant-sensitive Akt/mTOR pathway. We conclude that WZ37 can be a promising anti-cancer agent for the treatment of HNSCC.
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http://dx.doi.org/10.1016/j.tiv.2019.104754DOI Listing
June 2020

Transformation of phosphorus and stabilization of heavy metals during sewage sludge incineration: the effect of suitable additives and temperatures.

Environ Sci Pollut Res Int 2019 Oct 13;26(29):29917-29929. Epub 2019 Aug 13.

The Key Laboratory of Clean Energy Liaoning Province, Shenyang Aerospace University, Shenyang, China.

Phosphorus (P), an irreplaceable nutrient for all living organisms, is facing scarcity via phosphate resources. In this research, the effect of suitable additives and temperature on P and heavy metals speciation during sewage sludge (SS) thermochemical treatment was investigated. The results demonstrated that additives (CaO and MgO) could promote the conversion of non-apatite inorganic phosphorus (NAIP) to apatite phosphorus (AP). X-ray diffraction measurements indicated that the phosphorus mineral phase in sewage sludge ash (SSA) mainly was AP, with addition of MgO and CaO. Moreover, orthogonal testing revealed that the optimal molar ratio of Mg:Ca:P for P recovery as AP was 1:3.5:1 at 750 °C. Risk index results implied that the heavy metals in the phosphorus-enriched SSA have low potential ecological risk. Thermodynamic equilibrium calculations revealed that P reacted with the other metal ions was in the following order: Ca > Mg > Al > Fe > Zn > K. Graphical Abstract.
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http://dx.doi.org/10.1007/s11356-019-06146-2DOI Listing
October 2019

Conversion of Astrocytes and Fibroblasts into Functional Noradrenergic Neurons.

Cell Rep 2019 07;28(3):682-697.e7

Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address:

Dysfunction of noradrenergic (NA) neurons is associated with a number of neuronal disorders. Diverse neuronal subtypes can be generated by direct reprogramming. However, it is still unknown how to convert non-neuronal cells into NA neurons. Here, we show that seven transcription factors (TFs) (Ascl1, Phox2b, AP-2α, Gata3, Hand2, Nurr1, and Phox2a) are able to convert astrocytes and fibroblasts into induced NA (iNA) neurons. These iNA neurons express the genes required for the biosynthesis, release, and re-uptake of noradrenaline. Moreover, iNA neurons fire action potentials, receive synaptic inputs, and control the beating rate of co-cultured ventricular myocytes. Furthermore, iNA neurons survive and integrate into neural circuits after transplantation. Last, human fibroblasts can be converted into functional iNA neurons as well. Together, iNA neurons are generated by direct reprogramming, and they could be potentially useful for disease modeling and cell-based therapies.
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http://dx.doi.org/10.1016/j.celrep.2019.06.042DOI Listing
July 2019

Sirtuin 1 knockdown inhibits glioma cell proliferation and potentiates temozolomide toxicity via facilitation of reactive oxygen species generation.

Oncol Lett 2019 Jun 9;17(6):5343-5350. Epub 2019 Apr 9.

Department of Neurosurgery, The First Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong 515041, P.R. China.

Malignant glioma is one of the most common types of primary malignancies in the human central nervous system. Temozolomide (TMZ) is the most commonly used drug in clinical therapy of glioma; however, chemoresistance makes glioma difficult to cure and relapse likely. Sirtuin 1 (SIRT1) serves important roles in cell proliferation, differentiation and metabolism, but the role of SIRT1 in human glioma remains largely unexplored. In the present study, SIRT1 expression was assessed in human glioma tissues and cells. RNA interference and SIRT1 inhibitor were used to determine the effect of SIRT1 on glioma growth inhibition and glioma cell chemoresistance and . The levels of reactive oxygen species (ROS) in glioma cells were detected with the dihydroethidium probe following SIRT1 inhibition. The results demonstrated that SIRT1 was overexpressed in glioma tissues and cells, and patients with higher SIRT1 expression exhibited poorer prognosis. SIRT1 inhibition inhibited the proliferation of U87 and U251 cells. In addition, SIRT1 knockdown and SIRT1 inhibitor could significantly sensitize glioma cells to TMZ treatment and . The expression of Ki67 and p53 was demonstrated to be regulated by SIRT1. Finally, SIRT1 could regulate intracellular ROS generation in TMZ. In summary, SIRT1 was essential for glioma tumorigenesis and glioma cell chemoresistance. SIRT1 inhibition increased the sensitivity of glioma cells for TMZ via the facilitation of intracellular ROS generation, which suggested that SIRT1 may serve as a target for clinical therapy of glioma.
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http://dx.doi.org/10.3892/ol.2019.10235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6507466PMC
June 2019

Platelet endothelial aggregation receptor-1 regulates bovine muscle satellite cell migration and differentiation via integrin beta-1 and focal adhesion kinase.

Cell Adh Migr 2019 12;13(1):192-202

a The Laboratory of Cell and Developmental Biology , Northeast Agricultural University , Harbin , Heilongjiang , China.

PEAR1 is highly expressed at bovine MDSC differentiation. However, its biological function remains unclear. Western blotting results showed that PEAR1 increased between day 0 and day 2 of cell differentiation and decreased from day 3. Moreover, scratch test showed that wound healing rate increased after PEAR1 overexpression and decreased upon its suppression. Meanwhile, we found that, upon PEAR1 induction, both the expression of the focal adhesion-associated and MyoG, and the myotube fusion rate increased. However, when PEAR1 was suppressed, opposite results were obtained. Immunoprecipitation revealed an association between PEAR1 and ITGB1. Notably, inhibition of FAK and ITGB1 repressed cell differentiation. In conclusion, our study indicated that PEAR1 is involved in the regulation of bovine MDSC migration and differentiation.
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http://dx.doi.org/10.1080/19336918.2019.1619434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6550786PMC
December 2019

A New Antimicrobial Agent: Poly (3-hydroxybutyric acid) Oligomer.

Macromol Biosci 2019 05 5;19(5):e1800432. Epub 2019 Apr 5.

Research Centre for Smart Wearable Technology, Institute of Textiles and Clothing, Hong Kong Polytechnic University, Hong Kong, China.

In this work, it is first reported that the poly (3-hydroxybutyric acid) (PHB) oligomer with a few degrees of polymerization possesses effective antibacterial and antifungal properties. Two preparation methods for the PHB oligomer are described, namely, one-step ring-opening polymerization of β-butyrolactone and extraction from the fermented PHB polymer. An appropriate amount of the synthesized PHB oligomer shows no physiological toxicity to the skin and major organs of mice. Topological application of the synthesized PHB oligomer imparts antimicrobial ability to non-antibacterial fabrics with washing resistance. The synthesized PHB oligomer offers effective sterilization and promotes wound healing in infected nude mice. Most importantly, the PHB oligomer is also reactive to drug-resistant bacteria. These results suggest that the PHB oligomer is not only a great candidate for antimicrobial modification but also a promising one for biomedical applications. Finally, the antimicrobial mechanisms of the PHB oligomer are revealed, and these include disruption of biofilm and the bacterial wall/membrane, leakage of the intracellular content, inhibition of protein activity, and change in the transmembrane potential.
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http://dx.doi.org/10.1002/mabi.201800432DOI Listing
May 2019

EGFR-Targeted Immunotoxin Exerts Antitumor Effects on Esophageal Cancers by Increasing ROS Accumulation and Inducing Apoptosis via Inhibition of the Nrf2-Keap1 Pathway.

J Immunol Res 2018 25;2018:1090287. Epub 2018 Nov 25.

School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China.

Previously, we developed a novel EGFR-targeted antibody (denoted as Pan), which has superior antitumor activity against EGFR-overexpressed tumors. However, it shows marginal effect on the growth of esophageal cancers. Therefore, the variable region of Pan was fused to a fragment of Pseudomonas exotoxin A (PE38) to create the immunotoxin, denoted as Ptoxin (PT). Results indicated that PT shows more effective antitumor activity as compared with Pan both on EGFR-overexpressed KYSE-450 and KYSE-150 esophageal cancer cells, especially on KYSE-450 cells. Moreover, treatment of PT induces regression of KYSE-450 tumor xenografts in nude mice. Furthermore, we investigated the potential mechanism involved in the enhanced antitumor effects of PT. Data showed that PT was more potent in reducing the phosphorylation of EGFR and ERK1/2. More importantly, we for the first time found that PT was more effective than Pan in inducing ROS accumulation by suppression of the Nrf2-Keap1 antioxidant pathway, and then induced apoptosis in KYSE-450 esophageal cancer cells, which may partly explain the more sensitive response of KYSE-450 to PT treatment. To conclude, our study provides a promising therapeutic approach for immunotoxin-based esophageal cancer treatment.
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http://dx.doi.org/10.1155/2018/1090287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286775PMC
January 2019

A novel bispecific antibody fusion protein co-targeting EGFR and CD47 with enhanced therapeutic index.

Biotechnol Lett 2018 May 29;40(5):789-795. Epub 2018 Mar 29.

School of Basic Medical Sciences, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, 453000, Henan, People's Republic of China.

Objective: To promote targeting specificity of anti-CD47 agents, we have constructed a novel bispecific antibody fusion protein against EGFR and CD47, which may minimize the "off-target" effects caused by CD47 expression on red blood cells.

Results: The novel bispecific antibody fusion protein, denoted as Bi-SP could simultaneously bind to EGFR and CD47 and exhibited potent phagocytosis-stimulation effects in vitro. Bi-SP treatment with a low dose more effectively inhibited tumor growth than either EGFR-targeting antibody, Pan or the SIRPα variant-Fc (SIRPαV-Fc) in the A431 xenograft tumor model. In addition, the treatment with Bi-SP produced less red blood cell (RBC) losses than the SIRPαV-Fc treatment, suggesting its potential use for minimizing RBC toxicity in therapy.

Conclusions: Bi-SP with improved therapeutic index has the potential to treat CD47+ and EGFR+ cancers in clinics.
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http://dx.doi.org/10.1007/s10529-018-2535-2DOI Listing
May 2018

The novel dithiocarbamate, DpdtC suppresses HER2-overexpressed cancer cells by up-regulating NDRG1 via inactivation of HER2-ERK 1/2 signaling.

Sci Rep 2018 02 21;8(1):3398. Epub 2018 Feb 21.

School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China.

Dithiocarbamate has been tested for its effective anti-tumor activity, but the underlying mechanism remains unclear. We previously prepared a novel diththiocarbamate derivative, DpdtC with an ability of catalase inhibition. Here, we for the first time investigated the growth inhibition effects of DpdtC on HER2-amplified cancer cells and elucidated its mechanism of action. Results showed that DpdtC exerted the potent anti-tumor effects against HER2-overexpressed SK-OV-3 and SK-BR-3 cells, especially on SK-OV-3 cells with a higher NDRG1 level, which was also confirmed in the SK-OV-3 xenograft model. Interestingly, we observed that NDRG1 was up-regulated, while membrane expression of HER2 was regressed in SK-OV-3 cells upon DpdtC treatment. In agreement, silencing endogenous NDRG1 also increased the expression of HER2 in SK-OV-3 cells, while overexpressing NDRG1 decreased HER2 expression in SK-BR-3 cells. Furthermore, our results showed the formation of the EGFR/HER2 heterodimer was attenuated and phosphorylation of ERK1/2 was inhibited in SK-OV-3 cells when treated with DpdtC. Collectively, these observations demonstrated that NDRG1 plays an important role in mediating the inhibition effects of DpdtC in HER2-overexpressed cancer cells via selective targeting of the HER2-ERK1/2 pathway. Hence, our investigation suggests that up-regulation of NDRG1 by DpdtC is a promising therapeutic approach in HER2-overexpressed cancers.
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http://dx.doi.org/10.1038/s41598-018-21768-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821706PMC
February 2018

Synergistic anti-tumor activity of Nimotuzumab in combination with Trastuzumab in HER2-positive breast cancer.

Biochem Biophys Res Commun 2017 08 1;489(4):523-527. Epub 2017 Jun 1.

School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China. Electronic address:

Breast cancer is characterized with poor prognosis and high recurrence. HER2 is highly expressed in breast cancer and is a target for cancer therapy and prevention. Here, we investigated the anti-tumor activity of the combination of an HER2 inhibitor, trastuzumab with an EGFR-inhibitor, nimotuzumab in HER2-overexpressing breast cancer. Our data showed that a greater anti-tumor activity from the combination of trastuzumab and nimotuzumab than any alone usage of above antibody both in vitro and in vivo. Based on the combination index value, our data demonstrated that nimotuzumab synergistically enhanced trastuzumab-induced cell growth inhibition. Furthermore, we investigated the possible mechanism of this synergistic efficacy induced by trastuzumab plus nimotuzumab. Data showed that the combination was more potent in reducing the phosphorylation of HER2 and ERK1/2. We also found that the synergistic inhibition was partly attributed to the ROS generation and repression of NRF2 pathway that is known to promote cell growth. These results support the clinical development of this two-drug regimen for the treatment of HER2-amplified breast cancer.
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http://dx.doi.org/10.1016/j.bbrc.2017.06.001DOI Listing
August 2017

Downregulation of LKB1 promotes tumor progression and predicts unfavorable prognosis in patients with glioma.

Oncol Lett 2017 Mar 23;13(3):1688-1694. Epub 2017 Jan 23.

Department of Neurosurgery, The First Affiliated Hospital of Medical College, Shantou University, Shantou, Guangdong 515041, P.R. China.

The liver kinase B1 (LKB1)/5'-adenosine monophosphate-activated protein kinase pathway has been reported to facilitate glioma cell growth by improving growth conditions. To investigate the clinical significance of LKB1 in human gliomas western blot analysis and quantitative polymerase chain reaction experiments were performed. The present study demonstrated that LKB1 expression was markedly decreased at the messenger RNA and protein levels in 30 freshly prepared glioma tissues, compared with non-neoplastic brain tissues (P<0.001). Subsequently, immunohistochemical analysis demonstrated that LKB1 immunostaining in 180 glioma tissues was significantly decreased compared with that in the corresponding non-neoplastic brain tissues (P<0.001). Notably, this downregulation frequently occurred in high-grade gliomas, and statistical analysis revealed that low LKB1 expression was significantly associated with large tumor size (P=0.02), advanced World Health Organization grade (P=0.006) and low Karnofsky performance scale (P=0.01). The prognostic value of LKB1 expression in patients with glioma was additionally evaluated using Kaplan-Meier survival curves and Cox proportional hazards regression models. As a result, the overall survival time of patients with glioma with low LKB1 expression was shorter compared with that of patients with high LKB1 expression (P<0.001), and low LKB1 expression also indicated decreased survival time in patients with high-grade glioma (P<0.001). Collectively, the present data indicated that the downregulation of LKB1 was closely associated with the malignant degree of human gliomas, exhibiting lower expression at a higher grade. Notably, LKB1 may serve as a potential prognostic biomarker for patients with glioma following surgery.
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http://dx.doi.org/10.3892/ol.2017.5631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5403413PMC
March 2017

Transcription factor EGR1 promotes differentiation of bovine skeletal muscle satellite cells by regulating MyoG gene expression.

J Cell Physiol 2018 Jan 18;233(1):350-362. Epub 2017 May 18.

The Laboratory of Cell and Development, Northeast Agricultural University, XiangFang District, Harbin, Heilongjiang Province, China.

The transcription factor, early growth response 1 (EGR1), has important roles in various cell types in response to different stimuli. EGR1 is thought to be involved in differentiation of bovine skeletal muscle-derived satellite cells (MDSCs); however, the precise effects of EGR1 on differentiation of MDSCs and its mechanism of action remain unknown. In the present study, a time course of EGR1 expression and the effects of EGR1 on MDSC differentiation were determined. The results demonstrated that the expression of EGR1 mRNA and protein increased significantly in differentiating MDSCs relative to that in proliferating cells. Over-expression of the EGR1 gene in MDSCs promoted their differentiation and inhibited proliferation. Conversely, knock-down of EGR1 inhibited differentiation of MDSCs and promoted their proliferation, indicating that EGR1 promotes MDSC differentiation. Moreover, over-expression of EGR1 in MDSCs increased the expression of MyoG mRNA and protein, whereas its knock-down had the opposite effect. Furthermore, ChIP-PCR analyses demonstrated that EGR1 could bind directly to its putative binding site within the promoter region of MyoG, and determination of ERG1 subcellular localization in MDSCs demonstrated that it could relocate to the nucleus, indicating MyoG is likely an EGR1 target gene whose expression is positively regulated by this transcription factor. In conclusion, EGR1 can promote MDSC differentiation through positive regulation of MyoG gene expression.
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http://dx.doi.org/10.1002/jcp.25883DOI Listing
January 2018

Three-dimensional imaging of Drosophila motor synapses reveals ultrastructural organizational patterns.

J Neurogenet 2016 Sep - Dec;30(3-4):237-246

a Laboratory of Cell and Molecular Biology , University of Wisconsin-Madison , Madison , WI , USA.

We combined cryo-preservation of intact Drosophila larvae and electron tomography with comprehensive segmentation of key features to reconstruct the complete ultrastructure of a model glutamatergic synapse in a near-to-native state. Presynaptically, we detail a complex network of filaments that connects and organizes synaptic vesicles. We link the complexity of this synaptic vesicle network to proximity to the active zone cytomatrix, consistent with the model that these protein structures function together to regulate synaptic vesicle pools. We identify a net-shaped network of electron-dense filaments spanning the synaptic cleft that suggests conserved organization of trans-synaptic adhesion complexes at excitatory synapses. Postsynaptically, we characterize a regular pattern of macromolecules that yields structural insights into the scaffolding of neurotransmitter receptors. Together, these analyses reveal an unexpected level of conservation in the nanoscale organization of diverse glutamatergic synapses and provide a structural foundation for understanding the molecular machines that regulate synaptic communication at a powerful model synapse.
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http://dx.doi.org/10.1080/01677063.2016.1253693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5281062PMC
December 2017

Use of magnetic resonance imaging to assess ovarian maturation in live Rhinogobio ventralis (Sauvage & Dabry de Thiersant, 1874).

Theriogenology 2016 Nov 23;86(8):1969-74. Epub 2016 Jun 23.

Key Laboratory of Ecological Impacts of Hydraulic-projects and Restoration of Aquatic Ecosystem of Ministry of Water Resources, Institute of Hydroecology, Ministry of Water Resources & Chinese Academy of Sciences, Wuhan, People's Republic of China.

The aim of this study is to evaluate the application of magnetic resonance imaging (MRI) to assess ovarian maturation in live female Rhinogobio ventralis (Sauvage & Dabry de Thiersant, 1874). The fish were randomly collected from the Jiangjin area of the Yangtze River between January and April 2014. Magnetic resonance imaging was performed using a 3.0 T clinical MRI scanner with a brain coil and two pulse sequences (IDEAL and 3D CUBE) were employed. Magnetic resonance and histologic images at different stages of ovarian maturation (I-IV) were acquired. An empirical equation (y = -0.1 + 1.56 × x) was derived by traditional method to describe the relationship between the gonadosomatic index (y) and the percentage volume of the ovary (x). A significant correlation (R(2) = 0.977, P < 0.01, N = 53) was found between measurements of the percentage volume of the ovary by MRI and traditional methods. The research findings suggested that MRI was a reliable, rapid, and noninvasive method to assess stages of ovarian maturity in female R. ventralis.
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http://dx.doi.org/10.1016/j.theriogenology.2016.06.015DOI Listing
November 2016