Publications by authors named "Zheng Fan"

301 Publications

Remote characterization of surface slots by enhanced laser-generated ultrasonic Rayleigh waves.

Ultrasonics 2021 Oct 7;119:106595. Epub 2021 Oct 7.

School of Mechanical and Aerospace Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798, Singapore. Electronic address:

Characterization of surface features is essential in many industrial applications, especially for features with large depths, high aspect ratios or under extreme conditions. This work presents a non-contact method to characterize surface slots with large lengths using ultrasonic Rayleigh waves generated by a pulsed laser. A delay-and-sum superposition technique is applied to enhance the signal to noise ratio of transmitted Rayleigh waves. The length of the slot can be calculated from the time-of-flight information of Rayleigh waves without any prior knowledge of its orientation, width or aspect ratio. Both numerical simulations and experiments are conducted to demonstrate the proposed method, showing excellent performance. Furthermore, mode conversion has been studied to understand its impact on the reconstruction accuracy. Given the non-contact feature of the laser ultrasonic technique, the proposed method provides a simple and feasible avenue for the rapid characterisation of normal and angled surface features with high aspect ratio in extreme environments.
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http://dx.doi.org/10.1016/j.ultras.2021.106595DOI Listing
October 2021

Gelatin hydrogel/contact lens composites as rutin delivery systems for promoting corneal wound healing.

Drug Deliv 2021 Dec;28(1):1951-1961

Qingdao Eye Hospital of Shandong First Medical University, Qingdao, Shandong, China.

Corneal wound healing is a highly regulated biological process that is of importance for reducing the risk of blinding corneal infections and inflammations. Traditional eye drop was the main approach for promoting corneal wound healing. However, its low bioavailability required a high therapeutic concentration, which can lead to ocular or even systemic side effects. To develop a safe and effective method for treating corneal injury, we fabricated rutin-encapsulated gelatin hydrogel/contact lens composites by dual crosslinking reactions including free radical polymerization and carboxymethyl cellulose/-hydroxysulfosuccinimide crosslinking. drug release results evidenced that rutin in the composites could be sustainedly released for up to 14 days. In addition, biocompatibility assay indicated nontoxicity of the composites. Finally, the effect of rutin-encapsulated composites on the healing of the corneal injury in rabbits was investigated. The injury was basically cured in corneas using rutin-encapsulated composites (healing rate, 98.3% ± 0.7%) at 48 h post-operation, while the damage was still present in corneas using the composite (healing rate, 87.0% ± 4.5%). Further proteomics analysis revealed that corneal wound healing may be promoted by the ERK/MAPK and PI3K/AKT signal pathways. These results inform a potential intervention strategy to facilitate corneal wound healing in humans.
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http://dx.doi.org/10.1080/10717544.2021.1979126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475096PMC
December 2021

Trimetazidine and exercise provide comparable improvements to high fat diet-induced muscle dysfunction through enhancement of mitochondrial quality control.

Sci Rep 2021 Sep 27;11(1):19116. Epub 2021 Sep 27.

Division of Cardiac Rehabilitation, Department of Physical Medicine and Rehabilitation, Xiangya Hospital of Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, People's Republic of China.

Obesity induces skeletal muscle dysfunction. The pathogenesis of which appears to substantially involve mitochondrial dysfunction, arising from impaired quality control. Exercise is a major therapeutic strategy against muscle dysfunction. Trimetazidine, a partial inhibitor of lipid oxidation, has been proposed as a metabolic modulator for several cardiovascular pathologies. However, the effects of Trimetazidine on regulating skeletal muscle function are largely unknown. Our present study used cell culture and obese mice models to test a novel hypothesis that Trimetazidine could improve muscle atrophy with similar results to exercise. In C2C12 cells, high palmitic acid-induced atrophy and mitochondrial dysfunction, which could be reversed by the treatment of Trimetazidine. In our animal models, with high-fat diet-induced obesity associated with skeletal muscle atrophy, Trimetazidine prevented muscle dysfunction, corrected metabolic abnormalities, and improved mitochondrial quality control and mitochondrial functions similarly to exercise. Thus, our study suggests that Trimetazidine successfully mimics exercise to enhance mitochondrial quality control leading to improved high-fat diet-induced muscle dysfunction.
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http://dx.doi.org/10.1038/s41598-021-98771-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476493PMC
September 2021

Design, Modeling and Simulation of a Liquid Jet Gyroscope Based on Electrochemical Transducers.

Micromachines (Basel) 2021 Aug 24;12(9). Epub 2021 Aug 24.

Key Laboratory of Geo-Exploration Instrumentation, Ministry of Education, College of Instrumentation and Electrical Engineering, Jilin University, Changchun 130012, China.

We propose a novel liquid jet gyroscope based on electrochemical transducers, which uses electrolyte as the jet medium, and two electrochemical transducers placed symmetrically as the velocity measuring unit. The gyroscope includes a fluid pump to generate a jet flow, which flows into the jet chamber. Then, it is diverged into the shunt channels, pumped into reflux channels and merged by a fluid pump. The velocities of shunt flows are measured by two electrochemical transducers. The feasibility of the method was demonstrated in theory, and a 2D finite element model was built to simulate the dynamics of the liquid jet gyroscope. Simulation results confirm the effectiveness of the gyroscope, which has higher sensitivity in the near DC frequency band.
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http://dx.doi.org/10.3390/mi12091008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8467773PMC
August 2021

Modeling the Effect of Anisotropy in Ultrasonic Guided Wave Tomography.

IEEE Trans Ultrason Ferroelectr Freq Control 2021 Sep 22;PP. Epub 2021 Sep 22.

Most of the existing ultrasonic guided wave tomography approaches to map structural changes in plate-like waveguides are based on the assumption of an isotropic material model. However, there are many other engineering applications that are made of anisotropic materials and structures. Applying these techniques on such structures becomes complicated due to the anisotropic wave propagation behavior. The main challenge is to develop a suitable forward model that describes the wave propagation in such material, thereby enabling accurate reconstruction of the material properties. The present study proposes an anisotropic formulation of the acoustic forward model to map velocity variations induced by defects in anisotropic plates. The anisotropic behavior of the waves along the plate is simulated by implementing approximate anisotropic parameters. The velocity reconstruction is based on a full-waveform inversion algorithm, and its performance is investigated in the case of different degrees of anisotropy of the plate material and the defect. The results suggest that the method is highly suitable for imaging velocity changes due to defects. This is found to be the case when the defect has a similar anisotropic structure to the surrounding plate material. The validation experiment is performed on a multilayered composite plate with a circular defect of stiffness reduction using A0 mode, showing a very good performance of the reconstruction algorithm.
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http://dx.doi.org/10.1109/TUFFC.2021.3114432DOI Listing
September 2021

Synthesis and Bio-evaluation of 2-Alkyl Substituted Fluorinated Genistein Analogues Against Breast Cancer.

Med Chem 2021 Aug 29. Epub 2021 Aug 29.

Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China.

Background: Breast cancer is the leading cause of cancer death in women. The current methods of chemotherapy for breast cancer generally have strong adverse reactions and drug resistance. Therefore, the discovery of novel anti-breast cancer lead compounds is urgently needed.

Objective: Design and synthesize a series of 2-alkyl substituted fluorinated genistein analogues and evaluate their anti-breast cancer activity.

Methods: Target compounds were obtained in a multistep reaction synthesis. The anti-tumor activity of compounds I-1~I-35 were evaluated with MCF-7, MDA-MB-231, MDA-MB-435, and MCF-10A cell lines in vitro, with tamoxifen as the positive control. Molecular docking was used to study the interaction between the synthesized compounds and PI3K-gamma.

Results: A series of 2-alkyl substituted fluorinated genistein analogues were designed, synthesized and screened for their bioactivity. Most of the compounds displayed better selectivity toward breast cancer cell lines as compared with tamoxifen. Among these analogues, I-2, I-3, I-4, I-9, I-15 and I-17 have the strongest selective inhibition of breast cancer cells. Compounds I-10, I-13, I-15, I-17 and I-33 were found to have significant inhibitory effects on breast cancer cells. Molecular docking studies have shown that these compounds may act as PI3Kγ inhibitors and may further exhibit anti-breast cancer effects.

Conclusion: Most of the newly synthesized compounds could highly selectively inhibit breast cancer cell lines. The experimental results indicate that the synthesized analogs may also have obvious selective inhibitory effects on other malignant proliferation cancer cells.
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http://dx.doi.org/10.2174/1573406417666210830114715DOI Listing
August 2021

Exercise-induced angiogenesis is dependent on metabolically primed ATF3/4 endothelial cells.

Cell Metab 2021 Sep 5;33(9):1793-1807.e9. Epub 2021 Aug 5.

Laboratory of Exercise and Health, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH Zürich), Zürich 8603, Switzerland. Electronic address:

Exercise is a powerful driver of physiological angiogenesis during adulthood, but the mechanisms of exercise-induced vascular expansion are poorly understood. We explored endothelial heterogeneity in skeletal muscle and identified two capillary muscle endothelial cell (mEC) populations that are characterized by differential expression of ATF3/4. Spatial mapping showed that ATF3/4 mECs are enriched in red oxidative muscle areas while ATF3/4 ECs lie adjacent to white glycolytic fibers. In vitro and in vivo experiments revealed that red ATF3/4 mECs are more angiogenic when compared with white ATF3/4 mECs. Mechanistically, ATF3/4 in mECs control genes involved in amino acid uptake and metabolism and metabolically prime red (ATF3/4) mECs for angiogenesis. As a consequence, supplementation of non-essential amino acids and overexpression of ATF4 increased proliferation of white mECs. Finally, deleting Atf4 in ECs impaired exercise-induced angiogenesis. Our findings illustrate that spatial metabolic angiodiversity determines the angiogenic potential of muscle ECs.
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http://dx.doi.org/10.1016/j.cmet.2021.07.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432967PMC
September 2021

Mitochondrial fusion and fission are required for proper mitochondrial function and cell proliferation in fission yeast.

FEBS J 2021 Jul 26. Epub 2021 Jul 26.

CAS Center for Excellence in Molecular Cell Sciences, Ministry of Education Key Laboratory for Membrane-less Organelles & Cellular Dynamics, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.

Mitochondria form a branched tubular network in many types of cells, depending on a balance between mitochondrial fusion and fission. How mitochondrial fusion and fission are involved in regulating mitochondrial function and cell proliferation is not well understood. Here, we dissected the roles of mitochondrial fusion and fission in mitochondrial function and cell proliferation in fission yeast. We examined mitochondrial membrane potential by staining cells with DiOC and assessed mitochondrial respiration by directly measuring oxygen consumption of cells with a dissolved oxygen respirometer. We found that defects in mitochondrial fission or fusion reduce mitochondrial membrane potential and compromise mitochondrial respiration while the absence of both mitochondrial fusion and fission restores wild type-like respiration, normal membrane potential, and tubular networks of mitochondria. Moreover, we found that the absence of either mitochondrial fission or fusion prolongs the cell cycle and that the absence of both mitochondrial fusion and fission significantly delays cell cycle progression after nitrogen replenishment. The prolonged/delayed cell cycle is likely due to the deregulation of Cdc2 activation. Hence, our work not only establishes an intimate link between mitochondrial morphology and function but also underscores the importance of mitochondrial dynamics in regulating the cell cycle.
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http://dx.doi.org/10.1111/febs.16138DOI Listing
July 2021

Proteome plasticity in response to persistent environmental change.

Mol Cell 2021 08 21;81(16):3294-3309.e12. Epub 2021 Jul 21.

Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA; USC Leonard Davis School of Gerontology, University of Southern California, 3715 McClintock Ave., Los Angeles, CA 90191, USA. Electronic address:

Temperature is a variable component of the environment, and all organisms must deal with or adapt to temperature change. Acute temperature change activates cellular stress responses, resulting in refolding or removal of damaged proteins. However, how organisms adapt to long-term temperature change remains largely unexplored. Here we report that budding yeast responds to long-term high temperature challenge by switching from chaperone induction to reduction of temperature-sensitive proteins and re-localizing a portion of its proteome. Surprisingly, we also find that many proteins adopt an alternative conformation. Using Fet3p as an example, we find that the temperature-dependent conformational difference is accompanied by distinct thermostability, subcellular localization, and, importantly, cellular functions. We postulate that, in addition to the known mechanisms of adaptation, conformational plasticity allows some polypeptides to acquire new biophysical properties and functions when environmental change endures.
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http://dx.doi.org/10.1016/j.molcel.2021.06.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475771PMC
August 2021

The molecular basis for SARS-CoV-2 binding to dog ACE2.

Nat Commun 2021 07 7;12(1):4195. Epub 2021 Jul 7.

CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.

SARS-CoV-2 can infect many domestic animals, including dogs. Herein, we show that dog angiotensin-converting enzyme 2 (dACE2) can bind to the SARS-CoV-2 spike (S) protein receptor binding domain (RBD), and that both pseudotyped and authentic SARS-CoV-2 can infect dACE2-expressing cells. We solved the crystal structure of RBD in complex with dACE2 and found that the total number of contact residues, contact atoms, hydrogen bonds and salt bridges at the binding interface in this complex are slightly fewer than those in the complex of the RBD and human ACE2 (hACE2). This result is consistent with the fact that the binding affinity of RBD to dACE2 is lower than that of hACE2. We further show that a few important mutations in the RBD binding interface play a pivotal role in the binding affinity of RBD to both dACE2 and hACE2. Our work reveals a molecular basis for cross-species transmission and potential animal spread of SARS-CoV-2, and provides new clues to block the potential transmission chains of this virus.
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http://dx.doi.org/10.1038/s41467-021-24326-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263772PMC
July 2021

An unexpected complication in grade III internal hemorrhoids following treatment with cap-assisted endoscopic sclerotherapy.

Tech Coloproctol 2021 Jul 3. Epub 2021 Jul 3.

Department of Anorectal Surgery, People's Hospital of Deyang City, Deyang, Sichuan Province, China.

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http://dx.doi.org/10.1007/s10151-021-02491-yDOI Listing
July 2021

Association of Gender With Outcomes in Hospitalized Patients With 2019-nCoV Infection in Wuhan.

Front Public Health 2021 15;9:619482. Epub 2021 Jun 15.

Cardiovascular Medicine Department, Xiangya Hospital at Central South University, Changsha, China.

The aim of this study was to analyze the association of gender with psychological status and clinical outcomes among patients with 2019-nCoV infection to provide new directions for the prevention and control of the pandemic. One hundred and thirty-eight patients with confirmed 2019-nCoV infection at Wuhan Union Hospital, between February 8 and March 31, 2020, were included in the study analysis. General information and data on clinical characteristics were collected from patients' medical records. Participants' responses to self-report measures of psychological status were also collected. Anxiety levels, depression levels, and recovery rates were significantly higher among women compared to men. Conversely, chronic disease history and smoking rates, dry cough incidence, C-reactive protein levels, and disease severity were significantly higher among men than women ( < 0.05). Female patients experienced more severe psychological issues, due to higher levels of anxiety and stress, than male patients; indicating that more attention should be paid to the psychological care of female patients. In contrast, the general condition of male patients was more severe, particularly among elderly male patients with a history of chronic disease and smoking, suggesting that, to prevent and control 2019-nCoV infection, male patients should be encouraged to quit smoking as soon as possible to reduce the risk of severe pneumonia.
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http://dx.doi.org/10.3389/fpubh.2021.619482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239169PMC
July 2021

Synergistic bactericidal activities of tobramycin with ciprofloxacin and azithromycin against Klebsiella pneumoniae.

J Antibiot (Tokyo) 2021 08 28;74(8):528-537. Epub 2021 May 28.

State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Molecular Microbiology and Technology of the Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University, Tianjin, 300071, China.

Trans-translation is a unique bacterial ribosome rescue system that plays important roles in the tolerance to environmental stresses. It is composed of an ssrA-encoded tmRNA and a protein SmpB. In this study, we examined the role of trans-translation in antibiotic tolerance in Klebsiella pneumoniae and explored whether the inhibition of this mechanism could enhance the bactericidal activities of antibiotics. We found that deletion of the ssrA gene reduced the survival of K. pneumoniae after treatment with kanamycin, tobramycin, azithromycin, and ciprofloxacin, indicating an important role of the trans-translation in bacterial antibiotic tolerance. By using a modified ssrA gene with a 6×His tag we demonstrated that tobramycin suppressed the azithromycin and ciprofloxacin-elicited activation of trans-translation. The results were further confirmed with a trans-translation reporter system that is composed of a normal mCherry gene and a gfp gene without the stop codon. Compared to each individual antibiotic, combination of tobramycin with azithromycin or ciprofloxacin synergistically enhanced the killing activities against planktonic K. pneumoniae cells and improved bacterial clearance in a murine cutaneous abscess infection model. In addition, the combination of tobramycin and ciprofloxacin increased the bactericidal activities against biofilm-associated cells. Overall, our results suggest that the combination of tobramycin with azithromycin or ciprofloxacin is a promising strategy in combating K. pneumoniae infections.
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http://dx.doi.org/10.1038/s41429-021-00427-0DOI Listing
August 2021

Efficacy and safety of Lianhuaqingwen for mild or moderate coronavirus disease 2019: A meta-analysis of randomized controlled trials.

Medicine (Baltimore) 2021 May;100(21):e26059

Institute for Drug Evaluation, Peking University Health Science Center, Beijing, PR China.

Background: : Coronavirus disease 2019 (COVID-19) is an emerging and rapidly evolving disease, with no recommended effective anti-coronavirus treatments. Traditional Chinese Medicine (TCM) has been widely used to treat COVID-19 in China, and the most used one is Lianhuaqingwen (LH). This study aimed to assess the efficacy and safety of LH combined with usual treatment vs usual treatment alone in treating mild or moderate COVID-19 by a meta-analysis of randomized controlled trials (RCTs).

Methods And Analysis: : We systematically searched the Medline (OVID), Embase, the Cochrane Library, and 4 Chinese databases from inception to July 2020 to include the RCTs that evaluated the efficacy and safety of LH in combination with usual treatment vs usual treatment for mild or moderate COVID-19. A meta-analysis was performed to calculate the risk ratio (RR) and 95% confidence interval (CI) for binary outcomes and mean difference (MD) for continuous outcomes.

Results: : A total of 5 RCTs with 824 individuals with mild or moderate COVID 19 were included. Compared with the usual treatment alone, LH in combination with usual treatment significantly improved the overall clinical efficacy (RR = 2.39, 95% CI 1.61-3.55), increased the rate of recovery of chest computed tomographic manifestations (RR = 1.80, 95% CI 1.08-3.01), reduced the rate of conversion to severe cases (RR = 0.47, 95% CI 0.29-0.74), shorten the duration of fever (MD = -1.00, 95% CI -1.17 to -0.84). Moreover, LH in combination with usual treatment did not increase the occurrence of the adverse event compared to usual treatment alone.

Conclusion: : Our meta-analysis of RCTs indicated that LH in combination with usual treatment may improve the clinical efficacy in patients with mild or moderate COVID-19 without increasing adverse events. However, given the limitations and poor quality of included trials in this study, further large-sample RCTs or high-quality real-world studies are needed to confirm our conclusions.
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http://dx.doi.org/10.1097/MD.0000000000026059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154466PMC
May 2021

Targeting histone acetylation dynamics and oncogenic transcription by catalytic P300/CBP inhibition.

Mol Cell 2021 05;81(10):2183-2200.e13

The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, Australia.

To separate causal effects of histone acetylation on chromatin accessibility and transcriptional output, we used integrated epigenomic and transcriptomic analyses following acute inhibition of major cellular lysine acetyltransferases P300 and CBP in hematological malignancies. We found that catalytic P300/CBP inhibition dynamically perturbs steady-state acetylation kinetics and suppresses oncogenic transcriptional networks in the absence of changes to chromatin accessibility. CRISPR-Cas9 screening identified NCOR1 and HDAC3 transcriptional co-repressors as the principal antagonists of P300/CBP by counteracting acetylation turnover kinetics. Finally, deacetylation of H3K27 provides nucleation sites for reciprocal methylation switching, a feature that can be exploited therapeutically by concomitant KDM6A and P300/CBP inhibition. Overall, this study indicates that the steady-state histone acetylation-methylation equilibrium functions as a molecular rheostat governing cellular transcription that is amenable to therapeutic exploitation as an anti-cancer regimen.
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http://dx.doi.org/10.1016/j.molcel.2021.04.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183601PMC
May 2021

The PP2A-Integrator-CDK9 axis fine-tunes transcription and can be targeted therapeutically in cancer.

Cell 2021 Jun 17;184(12):3143-3162.e32. Epub 2021 May 17.

Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku FI-20014, Finland; Institute of Biomedicine, University of Turku, Turku FI-20014, Finland.

Gene expression by RNA polymerase II (RNAPII) is tightly controlled by cyclin-dependent kinases (CDKs) at discrete checkpoints during the transcription cycle. The pausing checkpoint following transcription initiation is primarily controlled by CDK9. We discovered that CDK9-mediated, RNAPII-driven transcription is functionally opposed by a protein phosphatase 2A (PP2A) complex that is recruited to transcription sites by the Integrator complex subunit INTS6. PP2A dynamically antagonizes phosphorylation of key CDK9 substrates including DSIF and RNAPII-CTD. Loss of INTS6 results in resistance to tumor cell death mediated by CDK9 inhibition, decreased turnover of CDK9 phospho-substrates, and amplification of acute oncogenic transcriptional responses. Pharmacological PP2A activation synergizes with CDK9 inhibition to kill both leukemic and solid tumor cells, providing therapeutic benefit in vivo. These data demonstrate that fine control of gene expression relies on the balance between kinase and phosphatase activity throughout the transcription cycle, a process dysregulated in cancer that can be exploited therapeutically.
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http://dx.doi.org/10.1016/j.cell.2021.04.022DOI Listing
June 2021

Functional landscape of SARS-CoV-2 cellular restriction.

Mol Cell 2021 06 13;81(12):2656-2668.e8. Epub 2021 Apr 13.

Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-5674, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029-5674, USA; Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029-5674, USA; The Tisch Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029-5674, USA.

A deficient interferon (IFN) response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been implicated as a determinant of severe coronavirus disease 2019 (COVID-19). To identify the molecular effectors that govern IFN control of SARS-CoV-2 infection, we conducted a large-scale gain-of-function analysis that evaluated the impact of human IFN-stimulated genes (ISGs) on viral replication. A limited subset of ISGs were found to control viral infection, including endosomal factors inhibiting viral entry, RNA binding proteins suppressing viral RNA synthesis, and a highly enriched cluster of endoplasmic reticulum (ER)/Golgi-resident ISGs inhibiting viral assembly/egress. These included broad-acting antiviral ISGs and eight ISGs that specifically inhibited SARS-CoV-2 and SARS-CoV-1 replication. Among the broad-acting ISGs was BST2/tetherin, which impeded viral release and is antagonized by SARS-CoV-2 Orf7a protein. Overall, these data illuminate a set of ISGs that underlie innate immune control of SARS-CoV-2/SARS-CoV-1 infection, which will facilitate the understanding of host determinants that impact disease severity and offer potential therapeutic strategies for COVID-19.
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http://dx.doi.org/10.1016/j.molcel.2021.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043580PMC
June 2021

Apolipoprotein M promotes cholesterol uptake and efflux from mouse macrophages.

FEBS Open Bio 2021 Jun 2;11(6):1607-1620. Epub 2021 May 2.

Clinical Medical Research Center, the Third Affiliated Hospital of Soochow University, Changzhou, China.

Apolipoprotein M (ApoM) exhibits various anti-atherosclerotic functions as a component of high-density lipoprotein (HDL) particles. Scavenger receptor class B type I (SR-BI) is a classic HDL receptor that mediates selective cholesterol uptake and enhances the efflux of cellular cholesterol to HDL. However, the effect of ApoM on cholesterol transport in macrophages remains unclear. In this study, we identified for the first time that ApoM is expressed in mouse macrophages and is involved in cholesterol uptake, similar to SR-BI. NBD-cholesterol uptake and efflux in cells were characterized using fluorescence spectrophotometry. The uptake ratios of cholesterol by macrophages from ApoM SR-BI mice were significantly lower than those from ApoM SR-BI and ApoM SR-BI mice. Real-time fluorescence quantitative PCR was used to analyze the expression of cholesterol transport-related genes involved in cholesterol uptake. ApoM-enriched HDL (ApoM HDL) facilitated more cholesterol efflux from murine macrophage Ana-1 cells than ApoM-free HDL (ApoM HDL). However, recombinant human ApoM protein inhibited the ability of ApoM HDL to induce cholesterol efflux. In conclusion, ApoM promotes cholesterol uptake and efflux in mouse macrophages. A better understanding of ApoM function may lead to the development of novel therapeutic strategies for treating atherosclerotic diseases.
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http://dx.doi.org/10.1002/2211-5463.13157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167864PMC
June 2021

Successful Implementation and Development of a Phase II Cardiac Rehabilitation Program: A China-Wide Cross-Sectional Study Tracking In-service Training Clinical Staff.

Front Public Health 2021 17;9:639273. Epub 2021 Mar 17.

Division of Cardiac Rehabilitation, Department of Physical Medicine and Rehabilitation, Xiangya Hospital of Central South University, Changsha, China.

Despite the benefits of cardiac rehabilitation (CR), phase II CR remains highly unavailable; the factors influential to the successful implementation and development of phase II CR programs have not been fully explored. A cross-sectional survey was completed by 168 nationwide clinical staff. Parameters associated with the successful implementation and development of phase II CR and the factors associated with the quality of CR were explored by multivariable logistic regression. One hundred and eighteen of 168 respondents' institutions had successfully developed phase II CR programs, 41 of which delivered high-quality CR. Independent factors associated with successful implementation and development of CR were leadership support from hospital administrators, support from resident physicians, staff perception in CR increasing medical risk, and department type (cardiology vs. rehabilitation department). Independent factors associated with CR quality were the availability of "professional CR providers" and staff perceptions of CR improving physician-patient relationships. The medical system factors did not affect the development and quality of CR, including hospital level, funding type, academic type, general/specialized hospital, located city, medical insurance, the existence of a CR outpatient clinic and independent space, the availability of professional CR providers, staff structure, and the availability of regular training and standard procedure. The development and quality of a phase II CR program may benefit from factors including support from administrators and resident physicians, adequately training more CR providers, without viewing medical system factors as a major issue.
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http://dx.doi.org/10.3389/fpubh.2021.639273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009984PMC
May 2021

A Voluntary Statewide Newborn Screening Pilot for Spinal Muscular Atrophy: Results from Early Check.

Int J Neonatal Screen 2021 Mar 21;7(1). Epub 2021 Mar 21.

RTI International, Research Triangle Park, Durham, NC 27709, USA.

Prior to statewide newborn screening (NBS) for spinal muscular atrophy (SMA) in North Carolina, U.S.A., we offered voluntary screening through the Early Check (EC) research study. Here, we describe the EC experience from October 2018 through December 2020. We enrolled a total of 12,065 newborns and identified one newborn with 0 copies of and two copies of , consistent with severe early onset of SMA. We also detected one false positive result, likely stemming from an unrelated blood disorder associated with a low white blood cell count. We evaluated the timing of NBS for babies enrolled prenatally ( = 932) and postnatally ( = 11,133) and reasons for delays in screening and reporting. Although prenatal enrollment led to faster return of results (median = 13 days after birth), results for babies enrolled postnatally were still available within a timeframe (median = 21 days after birth) that allowed the opportunity to receive essential treatment early in life. We evaluated an SMA q-PCR screening method at two separate time points, confirming the robustness of the assay. The pilot project provided important information about SMA screening in anticipation of forthcoming statewide expansion as part of regular NBS.
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http://dx.doi.org/10.3390/ijns7010020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006221PMC
March 2021

A chromosome-level genome of the spider Trichonephila antipodiana reveals the genetic basis of its polyphagy and evidence of an ancient whole-genome duplication event.

Gigascience 2021 Mar;10(3)

Key Laboratory of Eco-Environments in Three Gorges Reservoir Region (Ministry of Education), School of Life Sciences, Southwest University, No.2 Tiansheng Road, Beibei District, Chongqing 400715, China.

Background: The spider Trichonephila antipodiana (Araneidae), commonly known as the batik golden web spider, preys on arthropods with body sizes ranging from ∼2 mm in length to insects larger than itself (>20‒50 mm), indicating its polyphagy and strong dietary detoxification abilities. Although it has been reported that an ancient whole-genome duplication event occurred in spiders, lack of a high-quality genome has limited characterization of this event.

Results: We present a chromosome-level T. antipodiana genome constructed on the basis of PacBio and Hi-C sequencing. The assembled genome is 2.29 Gb in size with a scaffold N50 of 172.89 Mb. Hi-C scaffolding assigned 98.5% of the bases to 13 pseudo-chromosomes, and BUSCO completeness analysis revealed that the assembly included 94.8% of the complete arthropod universal single-copy orthologs (n = 1,066). Repetitive elements account for 59.21% of the genome. We predicted 19,001 protein-coding genes, of which 96.78% were supported by transcriptome-based evidence and 96.32% matched protein records in the UniProt database. The genome also shows substantial expansions in several detoxification-associated gene families, including cytochrome P450 mono-oxygenases, carboxyl/cholinesterases, glutathione-S-transferases, and ATP-binding cassette transporters, reflecting the possible genomic basis of polyphagy. Further analysis of the T. antipodiana genome architecture reveals an ancient whole-genome duplication event, based on 2 lines of evidence: (i) large-scale duplications from inter-chromosome synteny analysis and (ii) duplicated clusters of Hox genes.

Conclusions: The high-quality T. antipodiana genome represents a valuable resource for spider research and provides insights into this species' adaptation to the environment.
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http://dx.doi.org/10.1093/gigascience/giab016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7976613PMC
March 2021

Construction and theoretical insights into the ESIPT fluorescent probe for imaging formaldehyde in vitro and in vivo.

Chem Commun (Camb) 2021 Apr 10;57(28):3496-3499. Epub 2021 Mar 10.

Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, P. R. China.

We report the first ESIPT-based probe ABTB, for the highly sensitive and selective imaging of formaldehyde (FA). The various theoretical calculations have been systematically performed, and clearly unravel the lighting mechanism of the fluorescent probe for FA. Additionally, the probe was successfully applied in monitoring endogenous FA in the brain of AD mice.
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http://dx.doi.org/10.1039/d1cc00429hDOI Listing
April 2021

Evolution of Resistance to Phenazine Antibiotics in and Its Role During Coinfection with .

ACS Infect Dis 2021 03 2;7(3):636-649. Epub 2021 Mar 2.

State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Molecular Microbiology and Technology of the Ministry of Education, College of Life Sciences, Nankai University, Tianjin, 300071, China.

In the niches that and coinhabit, the later pathogen produces phenazine antibiotics to inhibit the growth of . Recently, a group of halogenated phenazines (HPs) has been shown to have potent antimicrobial activities against ; however, no HP-resistant mutant has been reported. Here, we demonstrate that develops HP-resistance via single amino acid change (Arg116Cys) in a transcriptional repressor TetR21. RNA-seq analysis showed that the TetR21 variation caused drastic up-regulation of an adjacent gene (halogenated phenazine resistance protein of ). Deletion of the in the TetR21 background restored bacterial susceptibility to HP, while overexpression in conferred HP-resistance. The expression of HprS is under tight transcriptional control of the TetR21 via direct binding to the promoter region of . The R116C mutation in TetR21 significantly reduced its DNA binding affinity. Moreover, natural phenazine antibiotics (phenazine-1-carboxylic acid and pyocyanin) and a HP analog (HP-22) are ligands for the TetR21, regulating its repressor activity. Combining homology analysis and LC-MS/MS assay we demonstrated that HprS is a phenazine efflux pump. To the best of our knowledge, we provide the first report of phenazine efflux pump in . Interestingly, the TetR21 variation has been found in some clinical isolates, and a laboratory strain of with TetR21 variation showed enhanced growth competitiveness toward and promoted coinfection with in the host environment, demonstrating significance of the mutation in host infections.
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http://dx.doi.org/10.1021/acsinfecdis.0c00837DOI Listing
March 2021

Identification of Novel PhoP-PhoQ Regulated Genes That Contribute to Polymyxin B Tolerance in .

Microorganisms 2021 Feb 9;9(2). Epub 2021 Feb 9.

State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Molecular Microbiology and Technology of the Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University, Tianjin 300071, China.

Polymyxin B and E (colistin) are the last resorts to treat multidrug-resistant Gram-negative pathogens. is intrinsically resistant to a variety of antibiotics. The PhoP-PhoQ two-component regulatory system contributes to the resistance to polymyxins by regulating an - operon that encodes lipopolysaccharide modification enzymes. To identify additional PhoP-regulated genes that contribute to the tolerance to polymyxin B, we performed a chromatin immunoprecipitation sequencing (ChIP-Seq) assay and found novel PhoP binding sites on the chromosome. We further verified that PhoP directly controls the expression of PA14_46900, PA14_50740 and PA14_52340, and the operons of PA14_11970-PA14_11960 and PA14_52350-PA14_52370. Our results demonstrated that mutation of PA14_46900 increased the bacterial binding and susceptibility to polymyxin B. Meanwhile, mutation of PA14_11960 (), PA14_11970 (), PA14_50740 (), PA14_52350 (), and PA14_52370 () reduced the bacterial survival rates and increased ethidium bromide influx under polymyxin B or Sodium dodecyl sulfate (SDS) treatment, indicating roles of these genes in maintaining membrane integrity in response to the stresses. By 1-N-phenylnaphthylamine (NPN) and propidium iodide (PI) staining assay, we found that and are involved in maintaining outer membrane integrity, and and - are involved in maintaining inner membrane integrity. Overall, our results reveal novel PhoP-PhoQ regulated genes that contribute to polymyxin B tolerance.
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http://dx.doi.org/10.3390/microorganisms9020344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916210PMC
February 2021

Emr1 regulates the number of foci of the endoplasmic reticulum-mitochondria encounter structure complex.

Nat Commun 2021 01 22;12(1):521. Epub 2021 Jan 22.

Ministry of Education Key Laboratory for Membrane-less Organelles & Cellular Dynamics, CAS Center for Excellence in Molecular Cell Sciences, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, 230027, Hefei, People's Republic of China.

The endoplasmic reticulum-mitochondria encounter structure (ERMES) complex creates contact sites between the endoplasmic reticulum and mitochondria, playing crucial roles in interorganelle communication, mitochondrial fission, mtDNA inheritance, lipid transfer, and autophagy. The mechanism regulating the number of ERMES foci within the cell remains unclear. Here, we demonstrate that the mitochondrial membrane protein Emr1 contributes to regulating the number of ERMES foci. We show that the absence of Emr1 significantly decreases the number of ERMES foci. Moreover, we find that Emr1 interacts with the ERMES core component Mdm12 and colocalizes with Mdm12 on mitochondria. Similar to ERMES mutant cells, cells lacking Emr1 display defective mitochondrial morphology and impaired mitochondrial segregation, which can be rescued by an artificial tether capable of linking the endoplasmic reticulum and mitochondria. We further demonstrate that the cytoplasmic region of Emr1 is required for regulating the number of ERMES foci. This work thus reveals a crucial regulatory protein necessary for ERMES functions and provides mechanistic insights into understanding the dynamic regulation of endoplasmic reticulum-mitochondria communication.
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http://dx.doi.org/10.1038/s41467-020-20866-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822926PMC
January 2021

Large-Area Synthesis and Patterning of All-Inorganic Lead Halide Perovskite Thin Films and Heterostructures.

Nano Lett 2021 Feb 19;21(3):1454-1460. Epub 2021 Jan 19.

Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States.

All-inorganic lead halide perovskites have attracted tremendous interest for their excellent stability when compared with hybrid perovskites. Here we report a large-area growth of monocrystalline all-inorganic perovskite thin films and further patterning them into heterostructure arrays. We show that highly oriented CsPbBr microcrystal domains can be readily grown on muscovite mica substrates with a well-defined epitaxial relationship, which can further expand and eventually merge into large-area monocrystalline CsPbBr thin films with an excellent optical quality. Taking a step further, we show the large-area CsPbBr thin film can be further patterned and selectively transformed into CsPbI using a selective anion-exchange process to produce CsPbBr-CsPbI lateral heterostructure arrays with spatially modulated photoluminescence emission and an apparent current rectification behavior. The capability to grow large-area CsPbBr monocrystalline thin films and heterostructure arrays defines a robust material platform for both the fundamental investigations and potential applications in optoelectronics.
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http://dx.doi.org/10.1021/acs.nanolett.0c04594DOI Listing
February 2021

Sestrin2 protects against bavachin induced ER stress through AMPK/mTORC1 signaling pathway in HepG2 cells.

J Pharmacol Sci 2021 Feb 26;145(2):175-186. Epub 2020 Nov 26.

Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China. Electronic address:

Bavachin (BV), a natural flavonoid compound derived from Psoralea corylifolia L, has been reported to be a potential hepatotoxin. Our previous studies have found that BV can induce endoplasmic reticulum (ER) stress-related cell apoptosis, but the molecular mechanism underlying BV-induced ER stress remains obscure. Sestrin2, a highly conserved stress-inducible protein, is involved in the cellular responses of various stress conditions and homeostatic regulation. However, whether Sestrin2 participated in the ER stress related hepatotoxicity against BV is still elusive. In the present study, we aim to investigate the role of BV on liver injury of mice and the impact of Sestrin2 on BV-induced ER stress in HepG2 cells. The results in mice showed that BV induced ER stress related liver injury with increased Sestrin2 expression involvement. Knockdown of Sestrin2 with siRNA aggravated BV-induced ER stress significantly in HepG2 cells. Further mechanistic study uncovered that inhibition of mTORC1 with rapamycin blocked BV-induced ER stress, and treatment with Sestrin2 siRNA blocked the inhibition effect of AMPK to mTORC1. Therefore, constant mTORC1 would lead to accumulation of misfolded or unfolded proteins and aggravated ER stress. Collectively, our study indicates that Sestrin2 confers protection against BV-induced ER stress via activating of the AMPK/mTORC1 pathway.
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http://dx.doi.org/10.1016/j.jphs.2020.11.012DOI Listing
February 2021
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