Publications by authors named "Shi Pan"

69 Publications

Diacylglycerol Kinase Inhibition Reduces Airway Contraction by Negative Feedback Regulation of Gq-signaling.

Am J Respir Cell Mol Biol 2021 Jul 22. Epub 2021 Jul 22.

Thomas Jefferson University, 6559, Center for Translational Medicine, Philadelphia, Pennsylvania, United States;

Exaggerated airway smooth muscle (ASM) contraction regulated by the Gq family of G protein-coupled receptors (GPCRs) causes airway hyperresponsiveness (AHR) in asthma. Activation of Gq-coupled GPCRs leads to phospholipase C (PLC)-mediated generation of inositol triphosphate (IP3) and diacylglycerol (DAG). DAG signaling is terminated by the action of DAG kinase (DGK) that converts DAG into phosphatidic acid (PA). Our previous study demonstrated that DGKα and ζ isoform knockout mice are protected from the development of allergen-induced AHR. Here we aimed at determining the mechanism by which DGK regulates ASM contraction. Activity of DGK isoforms was inhibited in human ASM cells by siRNA-mediated knockdown of DGKα and ζwhile pharmacological inhibition was achieved by pan DGK inhibitor I (R59022). Effects of DGK inhibition on contractile agonist-induced activation of PLC and myosin light chain (MLC) kinase, elevation of IP3, and calcium levels were assessed. Further, we employed human precision-cut lung slices and assessed the role of DGK in agonist-induced bronchoconstriction. DGK inhibitor I attenuated histamine- and methacholine-induced bronchoconstriction. DGKα and ζ knockdown or pre-treatment with DGK inhibitor I resulted in attenuated agonist-induced phosphorylation of MLC and myosin light chain phosphatase in ASM cells. Further, DGK inhibition decreased Gq agonist-induced calcium elevation, generation of IP3, and increased histamine-induced production of PA. Finally, DGK inhibition or treatment with DAG analog resulted in attenuation of activation of PLC in human ASM cells. Our findings suggest that DGK inhibition perturbed the DAG:PA ratio resulting in inhibition of Gq-PLC activation in a negative feedback manner, resulting in protection against ASM contraction.
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http://dx.doi.org/10.1165/rcmb.2021-0106OCDOI Listing
July 2021

Single-particle cryo-EM structural studies of the βAR-Gs complex bound with a full agonist formoterol.

Cell Discov 2020 Jul 7;6(1):45. Epub 2020 Jul 7.

Hefei National Laboratory of Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, 230026, Hefei, Anhui, China.

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http://dx.doi.org/10.1038/s41421-020-0176-9DOI Listing
July 2020

Chemical synthesis and biological activity of peptides incorporating an ether bridge as a surrogate for a disulfide bond.

Chem Sci 2020 Jul 8;11(30):7927-7932. Epub 2020 Jul 8.

School of Food and Biological Engineering, Hefei University of Technology Hefei Anhui 230009 China

Disulfide bridges contribute to the definition and rigidity of polypeptides, but they are inherently unstable in reducing environments and in the presence of isomerases and nucleophiles. Strategies to address these deficiencies, ideally without significantly perturbing the structure of the polypeptide, would be of great interest. One possible surrogate for the disulfide bridge is a simple thioether, but these are susceptible to oxidation. We report the introduction of an ether linkage into the biologically active, disulfide-rich peptides oxytocin, tachyplesin I, and conotoxin , using an ether-containing diaminodiacid as the key building block, obtained by the stereoselective ring-opening addition reaction of an aziridine skeleton with a hydroxy group. NMR studies indicated that the derivatives with an ether surrogate bridge exhibited very small change of their three-dimensional structures. The analogs obtained using this novel substitution strategy were found to be more stable than the original peptide in oxidative and reductive conditions; without a loss of bioactivity. This strategy is therefore proposed as a practical and versatile solution to the stability problems associated with cysteine-rich peptides.
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http://dx.doi.org/10.1039/d0sc02374dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163063PMC
July 2020

Anatomic study of carpal tunnel in adults using monoenergetic reconstruction of dual-energy computed tomography.

J Pak Med Assoc 2021 Feb;71(2(B)):663-671

Department of Radiology, Shengjing Hospital of China Medical University, Heping, Shenyang, China.

Objective: To seek optimal keV settings for imaging carpal tunnel in adults by dual-energy computed tomography (DECT) monoenergetic technique; to describe anatomic characteristics of carpal tunnel and to observe correlation between carpal bony and soft tissue structures.

Methods: DECT images of 20 wrists (11 left and 9 right wrists; 14 men, mean age 26.93±1.38 years, range 23 to 28, and 6 women, mean age 24.17 ± 0.98 years, range 23 to 26) were evaluated. Monoenergetic images were reconstructed at 42, 62, 82, 102, 122, and 142 keV. Image quality was assessed along a 5-point Likert scale, and the highest-quality images were chosen for quantitative analysis. Two musculoskeletal radiologists performed both analyses independently.

Results: The optimal energy spectrum with the best contrast-to-noise ratio (CNR) for monoenergetic images were at 62 keV (19 wrists, 95%) and 61 keV (1 wrist, 5%). There was substantial interobserver agreement between the readers in the 5-point Likert scale analysis of image quality (k= 0.793). Bland-Altman plots also indicated good agreement between observers in quantitative analysis. Intra-category 1 and 2 correlation was mostly discovered at hamate hook level and middle level of pisiform (P < 0.05), while bony and soft tissue structures partly reached correlation (P < 0.05).

Conclusions: The optimal energy spectrum for monoenergetic DECT imaging of carpal tunnel structures was 62 keV. DECT monoenergetic imaging could predict changes in soft tissue structures and demonstrate carpal tunnel anatomic structures.
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http://dx.doi.org/10.47391/JPMA.1203DOI Listing
February 2021

Structural mechanism of cooperative activation of the human calcium-sensing receptor by Ca ions and L-tryptophan.

Cell Res 2021 04 18;31(4):383-394. Epub 2021 Feb 18.

Hefei National Laboratory of Physical Sciences at Microscale, Anhui Laboratory of Advanced Photonic Science and Technology, and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, 230026, China.

The human calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor (GPCR) responsible for maintaining Ca homeostasis in the blood. The general consensus is that extracellular Ca is the principal agonist of CaSR. Aliphatic and aromatic L-amino acids, such as L-Phe and L-Trp, increase the sensitivity of CaSR towards Ca and are considered allosteric activators. Crystal structures of the extracellular domain (ECD) of CaSR dimer have demonstrated Ca and L-Trp binding sites and conformational changes of the ECD upon Ca/L-Trp binding. However, it remains to be understood at the structural level how Ca/L-Trp binding to the ECD leads to conformational changes in transmembrane domains (TMDs) and consequent CaSR activation. Here, we determined the structures of full-length human CaSR in the inactive state, Ca- or L-Trp-bound states, and Ca/L-Trp-bound active state using single-particle cryo-electron microscopy. Structural studies demonstrate that L-Trp binding induces the closure of the Venus flytrap (VFT) domain of CaSR, bringing the receptor into an intermediate active state. Ca binding relays the conformational changes from the VFT domains to the TMDs, consequently inducing close contact between the two TMDs of dimeric CaSR, activating the receptor. Importantly, our structural and functional studies reveal that Ca ions and L-Trp activate CaSR cooperatively. Amino acids are not able to activate CaSR alone, but can promote the receptor activation in the presence of Ca. Our data provide complementary insights into the activation of class C GPCRs and may aid in the development of novel drugs targeting CaSR.
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http://dx.doi.org/10.1038/s41422-021-00474-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115157PMC
April 2021

Episodic memory for food and non-food cues in females with obesity.

Eat Behav 2021 01 29;40:101472. Epub 2020 Dec 29.

Key Laboratory of Cognition and Personality (SWU), Ministry of Education, Chongqing 400715, China; Faculty of Psychology, Southwest University, Chongqing 400715, China; Research Center of Psychology and Social Development, Chongqing 400715, China. Electronic address:

Episodic memory is typically thought of as the memory system that makes possible mental time travel through subjective time. This may serve an important function in allowing us to use recent dietary information to predict future food needs and integrate this information with current food availability to adapt motivation accordingly. Growing evidence has suggested that episodic memory influences and is influenced by obesity. However, there is limited available evidence on the characteristics of episodic memory for food and non-food cues in people with obesity. The present study attempts to address this association and apply an episodic memory task to evaluate item memory and source memory for food and non-food cues in females with obesity. Participants were 26 females with obesity and 30 females with healthy weight, who were undergraduate students aged 17-24 years. They completed the Dutch Eating Behavior Questionnaire, hunger visual analog scale, fullness visual analog scale, desire-to-eat visual analog scale, and an episodic memory task including item memory and source memory. Results showed that the episodic memory patterns of females with and without obesity changed according to the type of stimuli. Specifically, females with obesity outperformed females with healthy weight in item memory for food cues, but showed deficits in item memory for non-food cues and source memory for both food and non-food cues. Taken together, based on the obesity and suboptimal food-related decision theoretical model, these findings are of great theoretical and clinical significance to explore episodic memory pattern differences between people with and without obesity.
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http://dx.doi.org/10.1016/j.eatbeh.2020.101472DOI Listing
January 2021

Association Between Susceptibility of Thrips palmi to Spinetoram and Frequency of G275E Mutation Provides Basis for Molecular Quantification of Field-Evolved Resistance.

J Econ Entomol 2021 02;114(1):339-347

Institute of Plant and Environmental Protection, Beijing Academy of Agricultural and Forestry Sciences, Haidian District, Beijing, China.

Putative mechanisms underlying spinosyn resistance have been identified in controlled studies on many species; however, mechanisms underlying field-evolved resistance and the development of a molecular diagnostic method for monitoring field resistance have lagged behind. Here, we examined levels of resistance of melon thrips, Thrips palmi Karny (Thysanoptera:Thripidae), to spinetoram as well as target site mutations in field populations across China to identify potential mechanisms and useful molecular markers for diagnostic and quantifying purposes. In resistant populations, we identified the G275E mutation, which has previously been linked to spinosyns resistance, and F314V mutation, both located in the α6 subunit of the nicotinic acetylcholine receptor. There was a strong correlation between levels of spinetoram resistance and allele frequency of G275E mutation in field-collected populations (r2 = 0.84) and those reared under laboratory conditions for two to five generations (r2 = 0.91). LC50 ranged from 0.12 to 0.66 mg/liter in populations without G275E mutation, whereas it ranged from 33.12 to 39.91 mg/liter in most populations with a G275E mutation frequency more than 90%. Our results indicate that the field-evolved resistance of T. palmi to spinetoram in China is mainly conferred by the G275E mutation. The frequency of the G275E mutation provides a useful diagnostic for quantifying resistance levels in field populations of T. palmi.
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http://dx.doi.org/10.1093/jee/toaa314DOI Listing
February 2021

Variable resistance to spinetoram in populations of across a small area unconnected to genetic similarity.

Evol Appl 2020 Oct 29;13(9):2234-2245. Epub 2020 May 29.

Institute of Plant and Environmental Protection Beijing Academy of Agriculture and Forestry Sciences Beijing China.

The melon thrips, , is an increasingly important pest of vegetables in northern China. Some populations have developed resistance in the field to the insecticide spinetoram. Understanding the origin and dispersal of insecticide-resistant populations can shed light on resistance management strategies. In this study, we tested susceptibility of seven greenhouse populations of to spinetoram collected from a small area of about 300 km in Shandong Province and examined population genetic structure across the area based on a segment of mitochondrial gene and 22 microsatellite loci to infer the possible origin and dispersal of insecticide resistance. Levels of resistance to spinetoram differed among seven populations, which included one population with high resistance (LC = 759.34 mg/L), three populations with medium resistance (LC ranged from 28.69 to 34.79 mg/L), and three populations with low resistance (LC ranged from 7.61 to 8.97 mg/L). The populations were genetically differentiated into two groups unrelated to both levels of resistance and geographic distance. The molecular data indicated high levels of gene flow between populations with different levels of resistance to spinetoram and low gene flow among populations with the same level of resistance, pointing to a likely separate history of resistance evolution. Resistance levels of two tested populations to spinetoram decreased 23 and 4.6 times after five generations without any exposure to the pesticide. We therefore suspect that resistance of most likely evolved in response to local applications of the insecticide. Our study suggests that the development of resistance could be avoided or resistance even reversed by reducing usage of spinetoram.
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http://dx.doi.org/10.1111/eva.12996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513702PMC
October 2020

Structural insights into human acid-sensing ion channel 1a inhibition by snake toxin mambalgin1.

Elife 2020 09 11;9. Epub 2020 Sep 11.

Tsinghua-Peking Joint Center for Life Sciences, Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Department of Chemistry, Tsinghua University, Beijing, China.

Acid-sensing ion channels (ASICs) are proton-gated cation channels that are involved in diverse neuronal processes including pain sensing. The peptide toxin Mambalgin1 (Mamba1) from black mamba snake venom can reversibly inhibit the conductance of ASICs, causing an analgesic effect. However, the detailed mechanism by which Mamba1 inhibits ASIC1s, especially how Mamba1 binding to the extracellular domain affects the conformational changes of the transmembrane domain of ASICs remains elusive. Here, we present single-particle cryo-EM structures of human ASIC1a (hASIC1a) and the hASIC1a-Mamba1 complex at resolutions of 3.56 and 3.90 Å, respectively. The structures revealed the inhibited conformation of hASIC1a upon Mamba1 binding. The combination of the structural and physiological data indicates that Mamba1 preferentially binds hASIC1a in a closed state and reduces the proton sensitivity of the channel, representing a closed-state trapping mechanism.
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http://dx.doi.org/10.7554/eLife.57096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553779PMC
September 2020

Single-particle cryo-EM structural studies of the βAR-Gs complex bound with a full agonist formoterol.

Cell Discov 2020 7;6:45. Epub 2020 Jul 7.

Hefei National Laboratory of Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, 230026 Hefei, Anhui China.

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http://dx.doi.org/10.1038/s41421-020-0176-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338445PMC
July 2020

A genetically encoded small-size fluorescent pair reveals allosteric conformational changes of G proteins upon its interaction with GPCRs by fluorescence lifetime based FRET.

Chem Commun (Camb) 2020 Jun;56(51):6941-6944

Hefei National Laboratory of Physical Science at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, 230027, P. R. China.

The dynamics of GPCRs (G protein-coupled receptors) coupling for cognate G proteins play a critical role in signal transduction. Herein, we reported a site-specifically labelled small-sized fluorescent pair 7-HC/FlAsH ((7-hydroxycoumarin-4-yl)-ethylglycine/fluorescein arsenical hairpin) for fluorescence lifetime based FRET (fluorescence resonance energy transfer) to reveal conformational differences of Gαi1 (inhibitory G proteins) and Gαs (stimulatory G proteins) upon β2AR (β2-adrenergic receptor) coupling. It offers a new generally applicable method to probe protein dynamic interactions or conformational changes.
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http://dx.doi.org/10.1039/d0cc02691cDOI Listing
June 2020

Chromosome-level assembly of the melon thrips genome yields insights into evolution of a sap-sucking lifestyle and pesticide resistance.

Mol Ecol Resour 2020 Jul 23;20(4):1110-1125. Epub 2020 Jun 23.

Institute of Plant and Environmental Protection, Beijing Academy of Agriculture and Forestry Sciences, Beijing, China.

Thrips are tiny insects from the order Thysanoptera (Hexapoda: Condylognatha), including many sap-sucking pests that are causing increasing damage to crops worldwide. In contrast to their closest relatives of Hemiptera (Hexapoda: Condylognatha), including numerous sap-sucking species, there are few genomic resources available for thrips. In this study, we assembled the first thrips genome at the chromosomal level from the melon thrips, Thrips palmi, a notorious pest in agriculture, using PacBio long-read and Illumina short-read sequences. The assembled genome was 237.85 Mb in size, with 1,324 contigs and a contig N50 of 567 kb. All contigs were assembled into 16 linkage groups assisted by the Hi-C technique. In total, 16,333 protein-coding genes were predicted, of which 88.13% were functionally annotated. Among sap-sucking insects, polyphagous species (e.g., T. palmi and Bemisia tabaci) usually possess more detoxification genes than oligophagous species (e.g., Diaphorina citri). The polyphagous thrips genomes characterized so far have relatively more detoxification genes in the GST and CCE families than polyphagous aphids, but they have fewer UGTs. HSP genes, especially from the Hsp70s group, have expanded in thrips compared to other hemipterans. These differences point to different genetic mechanisms associated with detoxification and stress responses in these two groups of sap-sucking insects. The expansion of these gene families may contribute to the rapid development of pesticide resistance in thrips, as supported by a transcriptome comparison of resistant and sensitive populations of T. palmi. The high-quality genome developed here provides an invaluable resource for understanding the ecology, genetics, and evolution of thrips as well as their relatives more generally.
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http://dx.doi.org/10.1111/1755-0998.13189DOI Listing
July 2020

PKG1α Cysteine-42 Redox State Controls mTORC1 Activation in Pathological Cardiac Hypertrophy.

Circ Res 2020 07 12;127(4):522-533. Epub 2020 May 12.

From the Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD (C.U.O., T.N., S.P., S.M., K.M.K.-S., B.L.L., A.C., G.Z., D.B., D.I.L., D.A.K., M.J.R.).

Rationale: Stimulated PKG1α (protein kinase G-1α) phosphorylates TSC2 (tuberous sclerosis complex 2) at serine 1365, potently suppressing mTORC1 (mechanistic [mammalian] target of rapamycin complex 1) activation by neurohormonal and hemodynamic stress. This reduces pathological hypertrophy and dysfunction and increases autophagy. PKG1α oxidation at cysteine-42 is also induced by these stressors, which blunts its cardioprotective effects.

Objective: We tested the dependence of mTORC1 activation on PKG1α C42 oxidation and its capacity to suppress such activation by soluble GC-1 (guanylyl cyclase 1) activation.

Methods And Results: Cardiomyocytes expressing wild-type (WT) PKG1α (PKG1α) or cysteine-42 to serine mutation redox-dead (PKG1α) were exposed to ET-1 (endothelin 1). Cells expressing PKG1α exhibited substantial mTORC1 activation (p70 S6K [p70 S6 kinase], 4EBP1 [elF4E binding protein-1], and Ulk1 [Unc-51-like kinase 1] phosphorylation), reduced autophagy/autophagic flux, and abnormal protein aggregation; all were markedly reversed by PKG1α expression. Mice with global knock-in of PKG1α subjected to pressure overload (PO) also displayed markedly reduced mTORC1 activation, protein aggregation, hypertrophy, and ventricular dysfunction versus PO in PKG1α mice. Cardioprotection against PO was equalized between groups by co-treatment with the mTORC1 inhibitor everolimus. TSC2-S1365 phosphorylation increased in PKG1α more than PKG1α myocardium following PO. TSC2 (TSC2 S1365 phospho-null, created by a serine to alanine mutation) knock-in mice lack TSC2 phosphorylation by PKG1α, and when genetically crossed with PKG1α mice, protection against PO-induced mTORC1 activation, cardiodepression, and mortality in PKG1α mice was lost. Direct stimulation of GC-1 (BAY-602770) offset disparate mTORC1 activation between PKG1α and PKG1α after PO and blocked ET-1 stimulated mTORC1 in TSC2-expressing myocytes.

Conclusions: Oxidation of PKG1α at C42 reduces its phosphorylation of TSC2, resulting in amplified PO-stimulated mTORC1 activity and associated hypertrophy, dysfunction, and depressed autophagy. This is ameliorated by direct GC-1 stimulation.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.315714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416445PMC
July 2020

Risk Factors for Facial Appearance Dissatisfaction Among Orthognathic Patients: Comparing Patients to a Non-Surgical Sample.

Front Psychol 2019 11;10:2775. Epub 2019 Dec 11.

Faculty of Psychology, Southwest University, Chongqing, China.

This study conducted a cross-sectional investigation of facial appearance dissatisfaction between patients before undergoing orthognathic surgery and a non-surgical sample to evaluate the potential influencing factors of facial appearance dissatisfaction. A sample of 354 participants completed a set of questionnaires concerning facial appearance dissatisfaction, interpersonal pressure, media pressure, and fear of negative appearance evaluation (112 patients, 242 controls). The patients reported higher facial appearance dissatisfaction, more media pressure, more interpersonal pressure, and a greater fear of negative appearance evaluation among others than the control group. Moreover, regression analyses identified interpersonal pressure and fear of negative appearance evaluation as the main predictors of facial appearance dissatisfaction whether in the orthognathic patients or the control groups. The associations between the perceptions of interpersonal pressure, fear of negative appearance evaluation, and facial appearance dissatisfaction support the possible utility of strengthening social experiences and psychological intervention in preventing and treating these appearance-concerns, especially for the orthognathic patients.
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http://dx.doi.org/10.3389/fpsyg.2019.02775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917591PMC
December 2019

Reply to Letter to the Editor: "Bnip3 as a potential target to treat airway smooth muscle remodeling in asthma?"

Am J Physiol Lung Cell Mol Physiol 2020 01;318(1):L213-L214

Center for Translational Medicine, Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia, Pennsylvania.

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http://dx.doi.org/10.1152/ajplung.00470.2019DOI Listing
January 2020

Free-electron-driven beam-scanning terahertz radiation.

Opt Express 2019 Sep;27(18):26192-26202

A beam-scanning terahertz (THz) radiation mechanism in a free-electron-driven grating system is proposed for THz applications. By loading a period-asynchronous rod array above the grating, the spoof surface plasmon (SSP) originally excited by the electron changes its radiation characteristics owing to the rod-induced Brillouin zone folding effect. The rod array functions as an antenna and converts the SSP into a spatial coherent THz radiation. The radiation frequency and direction can be precisely controlled by the electron energy. The field intensity of the radiation is increased approximately 20 times compared with that of the conventional Smith-Purcell radiation in the same frequency range. In addition, a microwave-band scaling prototype is fabricated and the frequency-controlled radiation is measured. Excellent agreement between the experimental and simulated results is obtained. This study paves the way for the development of on-chip THz sources for advanced communication and detection applications.
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http://dx.doi.org/10.1364/OE.27.026192DOI Listing
September 2019

Bnip3 regulates airway smooth muscle cell focal adhesion and proliferation.

Am J Physiol Lung Cell Mol Physiol 2019 12 11;317(6):L758-L767. Epub 2019 Sep 11.

Center for Translational Medicine, Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia, Pennsylvania.

Increased airway smooth muscle (ASM) mass is a key contributor to airway narrowing and airway hyperresponsiveness in asthma. Besides conventional pathways and regulators of ASM proliferation, recent studies suggest that changes in mitochondrial morphology and function play a role in airway remodeling in asthma. In this study, we aimed at determining the role of mitochondrial Bcl-2 adenovirus E1B 19 kDa-interacting protein, Bnip3, in the regulation of ASM proliferation. Bnip3 is a member of the Bcl-2 family of proteins critical for mitochondrial health, mitophagy, and cell survival/death. We found that Bnip3 expression is upregulated in ASM cells from asthmatic donors compared with that in ASM cells from healthy donors and transient downregulation of Bnip3 expression in primary human ASM cells using an siRNA approach decreased cell adhesion, migration, and proliferation. Furthermore, Bnip3 downregulation altered the structure (electron density) and function (cellular ATP levels, membrane potential, and reacitve oxygen species generation) of mitochondria and decreased expression of cytoskeleton proteins vinculin, paxillin, and actinin. These findings suggest that Bnip3 via regulation of mitochondria functions and expression of adhesion proteins regulates ASM adhesion, migration, and proliferation. This study reveals a novel role for Bnip3 in ASM functions and establishes Bnip3 as a potential target in mitigating ASM remodeling in asthma.
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http://dx.doi.org/10.1152/ajplung.00224.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957365PMC
December 2019

CuH-Catalyzed Asymmetric 1,6-Conjugate Reduction of -Quinone Methides: Enantioselective Synthesis of Triarylmethanes and 1,1,2-Triarylethanes.

Org Lett 2019 08 7;21(16):6397-6402. Epub 2019 Aug 7.

State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering , Lanzhou University , 222 Tianshui Nanlu , Lanzhou 730000 , China.

The first copper hydride (CuH)-catalyzed asymmetric 1,6-conjugate reduction of -quinone methides is reported. This protocol provides a new method to access a variety of triarylmethanes and 1,1,2-triarylethanes in good yields with excellent enantioselectivities and broad functional group tolerance.
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http://dx.doi.org/10.1021/acs.orglett.9b02308DOI Listing
August 2019

Field-evolved resistance and cross-resistance of the two-spotted spider mite, Tetranychus urticae, to bifenazate, cyenopyrafen and SYP-9625.

Exp Appl Acarol 2019 Apr 17;77(4):545-554. Epub 2019 Apr 17.

Institute of Plant and Environmental Protection, Beijing Academy of Agriculture and Forestry Sciences, 9 Shuguanghuayuan Middle Road, Haidian District, Beijing, 100097, China.

The acaricide bifenazate acts as complex III inhibitor whereas cyenopyrafen and SYP-9625 act as complex II inhibitors. All these acaricides are commonly used to control two-spotted spider mite (TSSM), Tetranychus urticae Koch. We examined field-evolved and laboratory-selected resistance of TSSM to these three acaricides and determined cross-resistance among them. Six field populations of TSSM showed low levels of resistance to bifenazate with resistance ratios ranging from 2.20 to 10.65 compared to a susceptible strain. SYP-9625, structurally similar to cyenopyrafen, showed slightly higher activity to TSSMs but significant cross-resistance in both field populations and a laboratory-selected strain by SYP-9625. However, low levels of resistance to these two chemicals were found in field populations even when used for short time periods. Cross-resistance was not found between bifenazate and Complex II inhibitors, cyenopyrafen and SYP-9625, in both field populations and the laboratory-selected strain. Field-evolved resistance of TSSM to the tested acaricides is still low and should be delayed by the implementation of resistance management practices. Cross-resistance between cyenopyrafen and SYP-9625 is obvious, so they should not be used together in resistance management strategies based on mode of action rotation.
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http://dx.doi.org/10.1007/s10493-019-00359-3DOI Listing
April 2019

Independently evolved and gene flow-accelerated pesticide resistance in two-spotted spider mites.

Ecol Evol 2019 Feb 3;9(4):2206-2219. Epub 2019 Feb 3.

Institute of Plant and Environmental Protection Beijing Academy of Agriculture and Forestry Sciences Beijing China.

Pest species are often able to develop resistance to pesticides used to control them, depending on how rapidly resistance can emerge within a population or spread from another resistant population. We examined the evolution of bifenazate resistance in China in the two-spotted spider mite (TSSM) Koch (Acari: Tetranychidae), one of the most resistant arthropods, by using bioassays, detection of mutations in the target gene, and population genetic structure analysis using microsatellite markers. Bioassays showed variable levels of resistance to bifenazate. The mutation G126S, which confers medium resistance in TSSM to bifenazate, had previously been detected prior to the application of bifenazate and was now widespread, suggesting likely resistance evolution from standing genetic variation. G126S was detected in geographically distant populations across different genetic clusters, pointing to the independent origin of this mutation in different TSSM populations. A novel A269V mutation linked to a low-level resistance was detected in two southern populations. Widespread resistance associated with a high frequency of the G126S allele was found in four populations from the Beijing area which were not genetically differentiated. In this case, a high level of gene flows likely accelerated the development of resistance within this local region, as well as into an outlying region distant from Beijing. These findings, therefore, suggest patterns consistent with both local evolution of pesticide resistance as well as an impact of migration, helping to inform resistance management strategies in TSSM.
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http://dx.doi.org/10.1002/ece3.4916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6392376PMC
February 2019

Regulation of ovarian cancer G protein-coupled receptor-1 expression and signaling.

Am J Physiol Lung Cell Mol Physiol 2019 05 6;316(5):L894-L902. Epub 2019 Feb 6.

Department of Medicine, Center for Translational Medicine and Division of Pulmonary, Allergy and Critical Care Medicine; and Jane & Leonard Korman Respiratory Institute, Thomas Jefferson University, Philadelphia, Pennsylvania.

Ovarian cancer G protein-coupled receptor 1 (OGR1) is a recently deorphanized G protein-coupled receptor shown to signal in response to low extracellular pH (↓pH) or certain benzodiazepines. The pleiotropic nature of OGR1 signaling in human airway smooth muscle (HASM) cells suggests that OGR1 is a potential therapeutic target for the management of obstructive lung diseases. However, the basic pharmacological and regulatory features of OGR1 remain poorly understood. We employed model systems of heterologously expressed [human embryonic kidney 293 (HEK293) cells] or endogenous (HASM) OGR1 to assess changes in expression, subcellular localization, and signaling capabilities following acute or chronic treatment with ↓pH or the benzodiazepines lorazepam and sulazepam. In HEK293 cells expressing OGR1, treatment with ↓pH and/or lorazepam, but not sulazepam, caused rapid OGR1 internalization. In HASM cells, acute treatment with ↓pH or benzodiazepines did not alter abundance of OGR1 mRNA; however, significant downregulation was observed following chronic treatment. Acute and chronic pretreatment of HASM cells with sulazepam or lorazepam resulted in receptor desensitization as demonstrated by reduced phosphorylation of vasodilator-stimulated phosphoprotein (VASP) or p42/p44 upon rechallenge. Acid (acute but not chronic) pretreatment of HASM cells induced desensitization of OGR1-mediated VASP (but not p42/p44) phosphorylation. In contrast to a recent study reporting OGR1 upregulation and sensitization in cardiac tissue subject to ischemic/acidic insult, chronic OGR1 activation in multiple model systems did not increase OGR1 expression or signaling capacity. The ability to induce OGR1 internalization and desensitization was activator dependent, reflecting the ability of different activators to induce specific receptor confirmations and engagement of specific heterotrimeric G proteins.
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http://dx.doi.org/10.1152/ajplung.00426.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589584PMC
May 2019

Mitochondrial regulation of airway smooth muscle functions in health and pulmonary diseases.

Arch Biochem Biophys 2019 03 8;663:109-119. Epub 2019 Jan 8.

Center for Translational Medicine, Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA. Electronic address:

Mitochondria are important for airway smooth muscle physiology due to their diverse yet interconnected roles in calcium handling, redox regulation, and cellular bioenergetics. Increasing evidence indicates that mitochondria dysfunction is intimately associated with airway diseases such as asthma, IPF and COPD. In these pathological conditions, increased mitochondrial ROS, altered bioenergetics profiles, and calcium mishandling contribute collectively to changes in cellular signaling, gene expression, and ultimately changes in airway smooth muscle contractile/proliferative properties. Therefore, understanding the basic features of airway smooth muscle mitochondria and their functional contribution to airway biology and pathology are key to developing novel therapeutics for airway diseases. This review summarizes the recent findings of airway smooth muscle mitochondria focusing on calcium homeostasis and redox regulation, two key determinants of physiological and pathological functions of airway smooth muscle.
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http://dx.doi.org/10.1016/j.abb.2019.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377851PMC
March 2019

Intraoral Prosthetic Chin Augmentation With Vertical Incisions.

J Craniofac Surg 2018 May;29(3):774-777

Department of Orthopedics, Taizhou First People's Hospital, Taizhou, China.

To explore a new surgical approach for chin augmentation using a prosthesis with 3 intraoral vertical incisions whereby placement of the prosthesis is more convenient and accurate, with fewer postoperative complications. Following the anatomic characteristics of the chin, a bilateral mucosal vertical incision and a median observation incision are made. The V-shaped mark on the upper side of the prosthesis can be seen through the observation incision after it is placed from the lateral incision into the predesigned compartment. The incision can be sutured if there is no bleeding in the operation area. Surgery performed in all 19 patients with mild microgenia with 6 to 12 months of follow-up resulted in satisfactory chin and face shape without any complications. The application of this novel method can correct McCarthy type I microgenia with more accurate positioning, less possibility of bilateral sideways and/or up/down movement, and fewer complications.
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http://dx.doi.org/10.1097/SCS.0000000000004252DOI Listing
May 2018

Broadband terahertz-power extracting by using electron cyclotron maser.

Sci Rep 2017 08 4;7(1):7265. Epub 2017 Aug 4.

School of Electronics Engineering and Computer Science, Peking University, Beijing, 100871, P. R. China.

Terahertz applications urgently require high performance and room temperature terahertz sources. The gyrotron based on the principle of electron cyclotron maser is able to generate watt-to-megawatt level terahertz radiation, and becomes an exceptional role in the frontiers of energy, security and biomedicine. However, in normal conditions, a terahertz gyrotron could generate terahertz radiation with high efficiency on a single frequency or with low efficiency in a relatively narrow tuning band. Here a frequency tuning scheme for the terahertz gyrotron utilizing sequentially switching among several whispering-gallery modes is proposed to reach high performance with broadband, coherence and high power simultaneously. Such mode-switching gyrotron has the potential of generating broadband radiation with 100-GHz-level bandwidth. Even wider bandwidth is limited by the frequency-dependent effective electrical length of the cavity. Preliminary investigation applies a pre-bunched circuit to the single-mode wide-band tuning. Then, more broadband sweeping is produced by mode switching in great-range magnetic tuning. The effect of mode competition, as well as critical engineering techniques on frequency tuning is discussed to confirm the feasibility for the case close to reality. This multi-mode-switching scheme could make gyrotron a promising device towards bridging the so-called terahertz gap.
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http://dx.doi.org/10.1038/s41598-017-07545-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5544717PMC
August 2017

Allosteric auto-inhibition and activation of the Nedd4 family E3 ligase Itch.

EMBO Rep 2017 09 26;18(9):1618-1630. Epub 2017 Jul 26.

Department of Neurosurgery, Huashan Hospital, Institutes of Biomedical Sciences, Fudan University, Shanghai, China

The Nedd4 family E3 ligases are key regulators of cell growth and proliferation and are often misregulated in human cancers and other diseases. The ligase activities of Nedd4 E3s are tightly controlled via auto-inhibition. However, the molecular mechanism underlying Nedd4 E3 auto-inhibition and activation is poorly understood. Here, we show that the WW domains proceeding the catalytic HECT domain play an inhibitory role by binding directly to HECT in the Nedd4 E3 family member Itch. Our structural and biochemical analyses of Itch reveal that the WW2 domain and a following linker allosterically lock HECT in an inactive state inhibiting E2-E3 transthiolation. Binding of the Ndfip1 adaptor or JNK1-mediated phosphorylation relieves the auto-inhibition of Itch in a WW2-dependent manner. Aberrant activation of Itch leads to migration defects of cortical neurons during development. Our study provides a new mechanism governing the regulation of Itch.
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http://dx.doi.org/10.15252/embr.201744454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5579370PMC
September 2017

HIV Incidence and Care Linkage among MSM First-Time-Testers in Shenyang, China 2012-2014.

AIDS Behav 2018 03;22(3):711-721

Key Laboratory of AIDS Immunology of National Health and Family Planning Commission, Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University, No 155, Nanjingbei Street, Heping District, Shenyang, 110001, Liaoning, China.

HIV testing is the first step to the fulfillment of Treat as Prevention (TasP) and reaching the 90-90-90 goal in HIV control. However, there are still a large number of Men who have Sex with Men (MSM) have never been tested for HIV before, and little is known about the HIV incidence and care linkage among this population. A Mixed method was used to recruit MSM who had never tested for HIV before from January 2012 to December 2014 in Shenyang, China. Potential MSM participants were invited to attend the enrollment for HIV and syphilis testing at a general hospital-based voluntary counseling and test (VCT). HIV confirmed positive subjects were further tested by BED HIV-1 capture enzyme immunoassay (BED-CEIA) to determine the HIV incidence. Syphilis was screened by the rapid plasma reagent test (RPR) and confirmed by Treponema pallidum particle assay (TPPA). All the HIV positive subjects were referred to the local Center for Disease Control and Prevention (CDC) and clinics for HIV primary care and follow-ups. In total 646 HIV first-time-testers of MSM (FMSM) attended this study, 73.4% (474/646) were aged under 31-year-old and 57.3% (370/646) and used the Internet as their major cruising avenue for seeking male sexual partners. The average prevalence of HIV and current syphilis infection was 10.8% (70/646) and 11.0% (71/646), respectively. The HIV incidence was 10.3 (95% confidence interval [CI] 6.1-14.5)/100PY. Multivariate logistic analysis showed that factors such as use of the Internet as the major cruising avenue (adjusted OR [AOR] 2.7, 95% CI 0.9-7.6) and having a current syphilis infection (AOR 4.2, 95% CI 1.8-12.2) were independent correlates of a recent HIV infection. Of the 95 HIV screening test positive FMSM, 73.7% (70/95) returned and be confirmed positive, 92.9% (65/70) of confirmed patients were linked to care. Among those retained and underwent CD4+ T cell test, 76.3% (42/55) started HIV antiretroviral therapy. Among the unconfirmed, 84.0% (21/25) were non-local migrants. The HIV incidence of FMSM in Shenyang was high. Future HIV testing program needs to keep on expanding among the MSM who have never been tested for HIV yet. The Internet-based campaigns and syphilis testing and treatment could represent an opportunity to get access to this hard-to-reach population and link them to HIV care. Future linkage to HIV care of this population should underscore the usage of HIV rapid diagnostic tests to prevent lost at early steps of linkage.
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http://dx.doi.org/10.1007/s10461-017-1840-4DOI Listing
March 2018

Bitter taste receptor agonists alter mitochondrial function and induce autophagy in airway smooth muscle cells.

Am J Physiol Lung Cell Mol Physiol 2017 07 27;313(1):L154-L165. Epub 2017 Apr 27.

Center for Translational Medicine, Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia, Pennsylvania

Airway remodeling, including increased airway smooth muscle (ASM) mass, is a hallmark feature of asthma and COPD. We previously identified the expression of bitter taste receptors (TAS2Rs) on human ASM cells and demonstrated that known TAS2R agonists could promote ASM relaxation and bronchodilation and inhibit mitogen-induced ASM growth. In this study, we explored cellular mechanisms mediating the antimitogenic effect of TAS2R agonists on human ASM cells. Pretreatment of ASM cells with TAS2R agonists chloroquine and quinine resulted in inhibition of cell survival, which was largely reversed by bafilomycin A1, an autophagy inhibitor. Transmission electron microscope studies demonstrated the presence of double-membrane autophagosomes and deformed mitochondria. In ASM cells, TAS2R agonists decreased mitochondrial membrane potential and increased mitochondrial ROS and mitochondrial fragmentation. Inhibiting dynamin-like protein 1 (DLP1) reversed TAS2R agonist-induced mitochondrial membrane potential change and attenuated mitochondrial fragmentation and cell death. Furthermore, the expression of mitochondrial protein BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 (Bnip3) and mitochondrial localization of DLP1 were significantly upregulated by TAS2R agonists. More importantly, inhibiting Bnip3 mitochondrial localization by dominant-negative Bnip3 significantly attenuated cell death induced by TAS2R agonist. Collectively the TAS2R agonists chloroquine and quinine modulate mitochondrial structure and function, resulting in ASM cell death. Furthermore, Bnip3 plays a central role in TAS2R agonist-induced ASM functional changes via a mitochondrial pathway. These findings further establish the cellular mechanisms of antimitogenic effects of TAS2R agonists and identify a novel class of receptors and pathways that can be targeted to mitigate airway remodeling as well as bronchoconstriction in obstructive airway diseases.
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http://dx.doi.org/10.1152/ajplung.00106.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538869PMC
July 2017

Bitter Taste Receptor Agonists Mitigate Features of Allergic Asthma in Mice.

Sci Rep 2017 04 11;7:46166. Epub 2017 Apr 11.

Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USA.

Asthma is characterized by airway inflammation, mucus secretion, remodeling and hyperresponsiveness (AHR). Recent research has established the bronchodilatory effect of bitter taste receptor (TAS2R) agonists in various models. Comprehensive pre-clinical studies aimed at establishing effectiveness of TAS2R agonists in disease models are lacking. Here we aimed to determine the effect of TAS2R agonists on features of asthma. Further, we elucidated a mechanism by which TAS2R agonists mitigate features of asthma. Asthma was induced in mice using intranasal house dust mite or aerosol ova-albumin challenge, and chloroquine or quinine were tested in both prophylactic and treatment models. Allergen challenge resulted in airway inflammation as evidenced by increased immune cells infiltration and release of cytokines and chemokines in the lungs, which were significantly attenuated in TAS2R agonists treated mice. TAS2R agonists attenuated features of airway remodeling including smooth muscle mass, extracellular matrix deposition and pro-fibrotic signaling, and also prevented mucus accumulation and development of AHR in mice. Mechanistic studies using human neutrophils demonstrated that inhibition of immune cell chemotaxis is a key mechanism by which TAS2R agonists blocked allergic airway inflammation and exerted anti-asthma effects. Our comprehensive studies establish the effectiveness of TAS2R agonists in mitigating multiple features of allergic asthma.
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http://dx.doi.org/10.1038/srep46166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5387415PMC
April 2017

Erratum to: Protein-protein interaction analysis in crude bacterial lysates using combinational method of F site-specific incorporation and F NMR.

Protein Cell 2018 06;9(6):592

Hefei National Laboratory for Physical Science at the Microscale School of Life Science, University of Science and Technology of China, Hefei, 230026, China.

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http://dx.doi.org/10.1007/s13238-017-0389-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966353PMC
June 2018

Internet-Based Sex-Seeking Behavior Promotes HIV Infection Risk: A 6-Year Serial Cross-Sectional Survey to MSM in Shenyang, China.

Biomed Res Int 2016 25;2016:2860346. Epub 2016 Dec 25.

Key Laboratory of AIDS Immunology of National Health and Family Planning Commission, Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University, Shenyang 110001, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China.

HIV prevalence is still rapidly increasing among Chinese men who have sex with men (MSM). The Internet also makes it easier for MSM to have casual partners. This study aims to evaluate the trend of Internet-based sex-seeking behavior of MSM and its impact on HIV prevalence, the distribution of HIV subtype strains, and transmitted drug resistance rates. A serial cross-sectional study was conducted from 2009 to 2014. Of the 1,981 MSM, 50.5% (1,000/1,981) mainly sought homosexual partners through the Internet (Internet-based MSM, IBM). The proportion of IBM among total MSM subjects increased from 43.3% to 61.5% ( < 0.001). HIV prevalence of IBM increased from 5.7% to 20.7%, while that of non-Internet-based MSM (NIBM) increased from 7.0% to 14.7%. A relative higher proportion of NIBM were infected with HIV CRF01_AE subtype than IBM (79.5% versus 72.2%, = 0.52). Multivariable analysis found IBM had a significantly higher HIV prevalence than NIBM (13.2% versus 10.5%, aOR = 1.4, 95% CI [1.0-1.9]). Being a migrant non-Shenyang resident MSM (aOR = 1.9, 95% CI [1.3-2.9]) and occasionally/never using condoms with casual homosexual partners (aOR = 1.7, 95% CI [1.1-2.6]) were two distinct risk factors for HIV infection in IBM. More efforts should be targeted towards developing interventions aimed at IBM, particularly migrant MSM and who engage in UAI with casual homosexual partners.
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http://dx.doi.org/10.1155/2016/2860346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5220408PMC
January 2017
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