Publications by authors named "Lixiang Wang"

225 Publications

Non-alcoholic fatty liver disease in mice with hepatocyte-specific deletion of mitochondrial fission factor.

Diabetologia 2021 May 29. Epub 2021 May 29.

Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Aims/hypothesis: Mitochondria are highly dynamic organelles continuously undergoing fission and fusion, referred to as mitochondrial dynamics, to adapt to nutritional demands. Evidence suggests that impaired mitochondrial dynamics leads to metabolic abnormalities such as non-alcoholic steatohepatitis (NASH) phenotypes. However, how mitochondrial dynamics are involved in the development of NASH is poorly understood. This study aimed to elucidate the role of mitochondrial fission factor (MFF) in the development of NASH.

Methods: We created mice with hepatocyte-specific deletion of MFF (MffLiKO). MffLiKO mice fed normal chow diet (NCD) or high-fat diet (HFD) were evaluated for metabolic variables and their livers were examined by histological analysis. To elucidate the mechanism of development of NASH, we examined the expression of genes related to endoplasmic reticulum (ER) stress and lipid metabolism, and the secretion of triacylglycerol (TG) using the liver and primary hepatocytes isolated from MffLiKO and control mice.

Results: MffLiKO mice showed aberrant mitochondrial morphologies with no obvious NASH phenotypes during NCD, while they developed full-blown NASH phenotypes in response to HFD. Expression of genes related to ER stress was markedly upregulated in the liver from MffLiKO mice. In addition, expression of genes related to hepatic TG secretion was downregulated, with reduced hepatic TG secretion in MffLiKO mice in vivo and in primary cultures of MFF-deficient hepatocytes in vitro. Furthermore, thapsigargin-induced ER stress suppressed TG secretion in primary hepatocytes isolated from control mice.

Conclusions/interpretation: We demonstrated that ablation of MFF in liver provoked ER stress and reduced hepatic TG secretion in vivo and in vitro. Moreover, MffLiKO mice were more susceptible to HFD-induced NASH phenotype than control mice, partly because of ER stress-induced apoptosis of hepatocytes and suppression of TG secretion from hepatocytes. This study provides evidence for the role of mitochondrial fission in the development of NASH.
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http://dx.doi.org/10.1007/s00125-021-05488-2DOI Listing
May 2021

Comment on: Slit-lamp examination during COVID-19: Where should the protective barrier be?

Indian J Ophthalmol 2021 06;69(6):1636-1637

Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, People's Republic of China.

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http://dx.doi.org/10.4103/ijo.IJO_34_21DOI Listing
June 2021

Poly(I:C) enhances the efficacy of phagocytosis checkpoint blockade immunotherapy by inducing IL-6 production.

J Leukoc Biol 2021 May 14. Epub 2021 May 14.

Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.

Macrophage phagocytosis plays essential roles in antitumor immunity. CD47/SIRPα phagocytosis checkpoint blockade has demonstrated therapeutic potential in several hematopoietic cancers, but recent clinical studies reported very limited efficacy against solid malignancies. Here, we show that polyinosinic-polycytidylic acid (Poly(I:C)), a synthetic analog of double-stranded RNA, enhances the antitumor activity of CD47 blockade in colorectal cancer in vitro and in vivo. Poly(I:C) activation leads to a potent immune response characterized by the production of proinflammatory cytokines, especially IL-6. Stimulation with IL-6 promotes the PI3K signaling and cytoskeletal reorganization required for macrophage phagocytosis mediated by CD47 blockade. Our findings demonstrate the potential of Poly(I:C) to synergize the efficacy of CD47 blockade therapy and a novel role for IL-6 in macrophage phagocytosis, which provide new strategy for combinational cancer immunotherapy.
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http://dx.doi.org/10.1002/JLB.5MA0421-013RDOI Listing
May 2021

Comment on "Ocular Manifestations of Hospitalized Patients with COVID-19 in Northeast of Iran".

Ocul Immunol Inflamm 2021 May 11. Epub 2021 May 11.

Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China.

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http://dx.doi.org/10.1080/09273948.2021.1903939DOI Listing
May 2021

Liquid biopsies to distinguish malignant from benign pulmonary nodules.

Thorac Cancer 2021 Jun 7;12(11):1647-1655. Epub 2021 May 7.

Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital, Anhui Medical University, Hefei, China.

Over the past decades, low-dose computed tomography (LD-CT) screening has been widely used for the early detection of lung cancer. Increasing numbers of indeterminate pulmonary nodules are now being discovered. However, it remains challenging to distinguish malignant from benign pulmonary nodules, especially those considered to be small or ground-glass (GGN) nodules. Liquid biopsies have been successfully applied in the diagnosis of advanced lung cancer, and the potential value for early detection of lung cancer has made great progress. Recent studies have demonstrated the value of various blood-based tumor biomarkers in determining the nature of pulmonary nodules, including cell-free DNA (cfDNA), microRNAs (miRNAs), circulating tumor cells (CTCs) and tumor-associated autoantibodies (AAbs). In this review, we summarize the latest progress of liquid biopsies, and their potential applications and challenges in the diagnosis of malignant pulmonary nodules.
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http://dx.doi.org/10.1111/1759-7714.13982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169297PMC
June 2021

A Distannylated Monomer of a Strong Electron-Accepting Organoboron Building Block: Enabling Acceptor-Acceptor-Type Conjugated Polymers for n-Type Thermoelectric Applications.

Angew Chem Int Ed Engl 2021 May 6. Epub 2021 May 6.

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China.

Acceptor-acceptor (A-A) copolymerization is an effective strategy to develop high-performance n-type conjugated polymers. However, the development of A-A type conjugated polymers is challenging due to the synthetic difficulty. Herein, a distannylated monomer of strong electron-deficient double B←N bridged bipyridine (BNBP) unit is readily synthesized and used to develop A-A type conjugated polymers by Stille polycondensation. The resulting polymers show ultralow LUMO energy levels of -4.4 eV, which is among the lowest value reported for organoboron polymers. After n-doping, the resulting polymers exhibit electric conductivity of 7.8 S cm and power factor of 24.8 μW m  K . This performance is among the best for n-type polymer thermoelectric materials. These results demonstrate the great potential of A-A type organoboron polymers for high-performance n-type thermoelectrics.
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http://dx.doi.org/10.1002/anie.202105127DOI Listing
May 2021

π-Stacked Donor-Acceptor Dendrimers for Highly Efficient White Electroluminescence.

Angew Chem Int Ed Engl 2021 May 3. Epub 2021 May 3.

Changchun Institute of Applied Chemistry Chinese Academy of Sciences: Chang Chun Institute of Applied Chemistry Chinese Academy of Sciences, State Key Laboratory of Polymer Physics and Chemistry, CHINA.

π-Stacked dendrimers consisting of cofacially aligned donors and acceptors are developed by introducing three dendritic teracridan donors with orthogonal configuration and three triazine acceptors in periphery of hexaphenylbenzene skeleton. The dendritic structure and orthogonal configuration of teracridan not only make their outer acridan segments approaching to acceptor in close distance, but also fix donor and acceptor in face-to-face alignment, leading to through-space charge transfer emission with thermally activated delayed fluorescence (TADF) effect. By regulating charge transfer strength via substituent effect of acceptor, emission color of the dendrimers can be tuned from blue to yellow/red region. Solution-processed two-color white organic light-emitting diodes (OLEDs) based on blue and yellow π-stacked donor-acceptor dendrimers exhibit the maximum external quantum efficiency of 20.6% and maximum power efficiency of 58.9 lm W -1 , representing the state-of-the-art efficiency for all-TADF white OLEDs by solution process.
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http://dx.doi.org/10.1002/anie.202104145DOI Listing
May 2021

Gut Structure and Microbial Communities in (Hymenoptera: Siricidae) and Their Predicted Contribution to Larval Nutrition.

Front Microbiol 2021 8;12:641141. Epub 2021 Apr 8.

Beijing Key Laboratory for Forest Pest Control, Beijing Forestry University, Beijing, China.

The European woodwasp, Fabricius, is a major invasive quarantine pest that attacks and kills pine trees outside of its native range. Insect gut structure and gut microbiota play crucial roles in various life activities. Despite a few reports in nutrition and survival, an extensive study on the larval gut microbiome is lacking. We studied the gut structure using a stereo microscope and used high throughput sequencing of the bacterial 16S rRNA genes and fungal internal transcribed spacer 2 (ITS2) regions to investigate gut microbiota in different developmental stages of , including larvae, adults, and larval frass. We used PICRUSt2 to predict the functional profiles. The larval gut was thin and thread-like from the oral cavity to the anus, carrying few xylem particles in the crop. , , and s.l were the dominant bacteria in the guts of larvae, adults, and frass, respectively. Even though was the most abundant among all bacteria, , , and , which might be involved in degrading organic matter and fixing nitrogen occurred exclusively in the larval gut indicating their possible role in the growth and development of larvae in pine tree xylem. Fungal communities did not change significantly across different developmental stages or the frass. was dominant in the woodwasp's larval gut. Functional prediction of bacterial and fungal communities revealed that they may encod enzymes involved in degrading lignocellulose and fixing nitrogen. Ours is the first study that compares gut microbial communities present in larvae, adults, and frass. This study could provide an understanding of larval nutrient acquisition in nutrient-deficient host xylem to some extent. Our study may unlock novel strategies for the development of pest management approaches based on interfering with the gut microbiota and restricting their role in larval survival and development.
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http://dx.doi.org/10.3389/fmicb.2021.641141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060704PMC
April 2021

An Emphasis on the Gap Between the Surveyed Myopia Rate and Eyeglass-Wearing Rate in the Study of Ocular Susceptibility to SARS-CoV-2 Infection.

JAMA Ophthalmol 2021 05;139(5):586-587

Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, People's Republic of China.

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http://dx.doi.org/10.1001/jamaophthalmol.2021.0494DOI Listing
May 2021

Analysis of Chronic Mild Stress-Induced Hypothalamic Proteome: Identification of Protein Dysregulations Associated With Vulnerability and Resiliency to Depression or Anxiety.

Front Mol Neurosci 2021 2;14:633398. Epub 2021 Mar 2.

Institute of Neuroscience, Chongqing Medical University, Chongqing, China.

Chronic stress as a known risk factor leads to hyperactivity of the hypothalamus-pituitary-adrenal (HPA) axis in both depression and anxiety. However, the stress-induced dysfunction of the HPA axis in these disorders especially the common and unique molecular dysregulations have not been well-explored. Previously, we utilized a chronic mild stress (CMS) paradigm to segregate and gain depression-susceptible, anxiety-susceptible, and insusceptible groups. In this study, we continue to examine the possible protein expression alterations of the hypothalamus as the center of the HPA axis in these three groups by using a proteomic approach. Though isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative analysis, a total of 593 dysregulated proteins were identified. These were potentially associated with vulnerability and adaptability of CMS-caused depression or anxiety and therefore might become novel investigative protein targets. Further independent analysis using parallel reaction monitoring (PRM) indicated that 5, 7, and 21 dysregulated proteins were specifically associated with depression-susceptible, anxiety-susceptible, and insusceptible groups, respectively, suggesting that the same CMS differently affected the regulation system of the rat hypothalamic proteome. In summary, the current proteomic research on the hypothalamus provided insights into the specific and common molecular basis for the HPA dysfunction mechanisms that underlie resiliency and vulnerability to stress-induced depression or anxiety.
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http://dx.doi.org/10.3389/fnmol.2021.633398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960925PMC
March 2021

Clodronate, an inhibitor of the vesicular nucleotide transporter, ameliorates steatohepatitis and acute liver injury.

Sci Rep 2021 Mar 4;11(1):5192. Epub 2021 Mar 4.

Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan.

The vesicular nucleotide transporter (VNUT) is responsible for the vesicular storage and release of ATP from various ATP-secreting cells, and it plays an essential role in purinergic signaling. Although extracellular ATP and its degradation products are known to mediate various inflammatory responses via purinoceptors, whether vesicular ATP release affects steatohepatitis and acute liver injury is far less understood. In the present study, we investigated the effects of clodronate, a potent and selective VNUT inhibitor, on acute and chronic liver inflammation in mice. In a model of methionine/choline-deficient diet-induced non-alcoholic steatohepatitis (NASH), the administration of clodronate reduced hepatic inflammation, fibrosis, and triglyceride accumulation. Clodronate also protected mice against high-fat/high-cholesterol diet-induced steatohepatitis. Moreover, prophylactic administration of clodronate prevented D-galactosamine and lipopolysaccharide-induced acute liver injury by reducing inflammatory cytokines and hepatocellular apoptosis. In vitro, clodronate inhibited glucose-induced vesicular ATP release mediated by VNUT and reduced the intracellular level and secretion of triglycerides in isolated hepatocytes. These results suggest that VNUT-dependent vesicular ATP release plays a crucial role in the recruitment of immune cells, cytokine production, and the aggravation of steatosis in the liver. Pharmacological inhibition of VNUT may provide therapeutic benefits in liver inflammatory disorders, including NASH and acute toxin-induced injury.
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http://dx.doi.org/10.1038/s41598-021-83144-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933178PMC
March 2021

Application of Multimodal and Molecular Imaging Techniques in the Detection of Choroidal Melanomas.

Front Oncol 2020 1;10:617868. Epub 2021 Feb 1.

Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China.

Choroidal melanomas are the most common ocular malignant tumors worldwide. The onset of such tumors is insidious, such that affected patients often have no pain or obvious discomfort during early stages. Notably, enucleation is required for patients with a severe choroidal melanoma, which can seriously impact their quality of life. Moreover, choroidal melanomas metastasize early, often to the liver; this eventually causes affected patients to die of liver failure. Therefore, early diagnosis of choroidal melanomas is extremely important. Unfortunately, an early choroidal melanoma is easily confused with a choroidal nevus, which is the most common benign tumor of the eye and does not often require surgical treatment. This review discusses recent advances in the use of multimodal and molecular imaging to identify choroidal melanomas and choroidal nevi, detect early metastasis, and diagnose patients with choroidal melanomas.
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http://dx.doi.org/10.3389/fonc.2020.617868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902045PMC
February 2021

Chronic mild stress-induced protein dysregulations correlated with susceptibility and resiliency to depression or anxiety revealed by quantitative proteomics of the rat prefrontal cortex.

Transl Psychiatry 2021 Feb 24;11(1):143. Epub 2021 Feb 24.

Institute of Neuroscience, Chongqing Medical University, 400016, Chongqing, China.

Chronic stress is a significant risk factor for depression as well as anxiety disorders. Yet, the stress-induced specific and common molecular dysregulations of these disorders have not been fully understood. Previously, we constructed a chronic mild stress (CMS) rat model to separate and obtain depression-susceptible, anxiety-susceptible, and insusceptible groups. In this study, the prefrontal cortical proteomes of the three stressed groups were comparatively profiled utilizing isobaric tags for relative and absolute quantitation (iTRAQ)-coupled tandem mass spectrometry approach. A total of 212 protein dysregulations were identified, potentially correlating to susceptibility or resilience to CMS-induced depression or anxiety, and thus might serve as potential protein targets for further investigation. In addition, independent analysis by parallel reaction monitoring identified changes in Gfap, Rhog, Gnai2, Ppp1r1b, and Uqcrh; Tubb6, Urod, Cul1, Spred1, and Gpcpd1; Acadl, Ppp1r1a, Grm2, Mtor, Lsm8, Cplx2, and Tsta3 that were distinctly correlated to depression-susceptible, anxiety-susceptible, or insusceptible groups, respectively. This suggested that identical CMS had different effects on the protein regulation system of the rat prefrontal cortex. Collectively, the present proteomics study of the prefrontal cortex established a significant molecular basis and offered new insights into the specificity and commonality of pathophysiologic mechanisms underlying susceptibility and resiliency to stress-induced depression or anxiety.
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http://dx.doi.org/10.1038/s41398-021-01267-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904772PMC
February 2021

Development of L-carnosine functionalized iron oxide nanoparticles loaded with dexamethasone for simultaneous therapeutic potential of blood brain barrier crossing and ischemic stroke treatment.

Drug Deliv 2021 Dec;28(1):380-389

Internal Medicine-Neurology, Liaocheng People's Hospital, Liaocheng, PR China.

The development of suitable drug delivery carriers is significant in biomedical applications to improve the therapeutic efficiency. Recent progress in nanotechnological fields, paved the way for the formulation of variety of drug carriers. The brain disorders such as ischemic stroke, brain cancer, and CNS disorders were poorly treated due to the presence of blood brain barrier that hinders the passage of drugs to the brain. Hence, the formulated drugs should have the ability to cross the blood-brain barrier (BBB) for ischemic stroke treatment. In the present work, we have synthesized PLGA functionalized magnetic FeO nanoparticle (MNP) with L-carnosine peptide (LMNP) composite loaded with dexamethasone ([email protected]) and demonstrated as efficient drug delivery platform for simultaneous BBB crossing and treatment of ischemic stroke. The surface morphology, particles size and zeta potential of the prepared material was studied from SEM, PSD, PDI and TEM analyses. The drug loading of dexamethasone in LMNP ([email protected]) vesicles was found to be 95.6 ± 0.2%. The drug release kinetics displayed that prepared composited LMNP material provides controlled and sustainable releasing efficiency at pH 7.4 and 5.8 when compared to the PLGA NPs and free dexamethasone drug molecules. The cytotoxicity and the biocompatibility test results were found to be satisfactory. The L-carnosine loaded nano-formulation has been greatly leads to effective BBB crossing to access the brain tissues. These results showed that the FeO nanoparticles/PLGA polymer can be used as an effective drug carrier for the treatment of stroke and simultaneous blood brain barrier crossing.
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http://dx.doi.org/10.1080/10717544.2021.1883158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891889PMC
December 2021

Sterically-Locked Donor-Acceptor Conjugated Polymers Showing Efficient Thermally Activated Delayed Fluorescence.

Angew Chem Int Ed Engl 2021 Apr 16;60(17):9635-9641. Epub 2021 Mar 16.

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China.

Donor-acceptor (D-A) conjugated polymers often possess a significant frontier molecular orbital overlap because of the conjugation elongation, leading to no thermally activated delayed fluorescence (TADF) caused by a large singlet-triplet energy splitting (▵E ). Herein a novel steric locking strategy is proposed by incorporating methyl groups into D-A conjugated polymers. Benefitting from the methyl hindrance, the torsion between the donor and acceptor can be well tuned to form a sterically-locked conformation, so that the unwanted relaxation toward planarity and thus conjugation elongation is prevented to boost hole-electron separation. The resultant D-A conjugated polymer achieves an extremely low ΔE of 0.09 eV to enable efficient TADF. The corresponding doped and non-doped devices are fabricated via a solution process, revealing a record-high external quantum efficiency (EQE) of 24.0 % (79.4 cd A , 75.0 lm W ) and 15.3 % (50.9 cd A , 47.3 lm W ).
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http://dx.doi.org/10.1002/anie.202016428DOI Listing
April 2021

Dynamin-related protein 1 inhibition reduces hepatic PCSK9 secretion.

Cardiovasc Res 2021 Feb 1. Epub 2021 Feb 1.

Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, 02115, USA.

Aims: Proteostasis maintains protein homeostasis and participates in regulating critical cardiometabolic disease risk factors, including proprotein convertase subtilisin/kexin type 9 (PCSK9). Endoplasmic reticulum (ER) remodeling through release and incorporation of trafficking vesicles mediates protein secretion and degradation. We hypothesized that ER remodeling that drives mitochondrial fission participates in cardiometabolic proteostasis.

Methods And Results: We used in vitro and in vivo hepatocyte inhibition of a protein involved in mitochondrial fission, dynamin-related protein 1 (DRP1). Here, we show that DRP1 promotes remodeling of select ER microdomains by tethering vesicles at ER. A DRP1 inhibitor, mitochondrial division inhibitor 1 (mdivi-1) reduced ER localization of a DRP1 receptor, mitochondrial fission factor, suppressing ER remodeling-driven mitochondrial fission, autophagy, and increased mitochondrial calcium buffering and PCSK9 proteasomal degradation. DRP1 inhibition by CRISPR/Cas9 deletion or mdivi-1 alone or in combination with statin incubation in human hepatocytes and hepatocyte-specific Drp1-deficiency in mice reduced PCSK9 secretion (-78.5%). In HepG2 cells, mdivi-1 increased low-density lipoprotein receptor via c-Jun transcription and reduced PCSK9 mRNA levels via suppressed sterol regulatory binding protein-1c. Additionally, mdivi-1 reduced macrophage burden, oxidative stress, and advanced calcified atherosclerotic plaque in aortic roots of diabetic Apoe-deficient mice and inflammatory cytokine production in human macrophages.

Conclusions: We propose a novel tethering function of DRP1 beyond its established fission function, with DRP1-mediated ER remodeling likely contributing to ER constriction of mitochondria that drives mitochondrial fission. We report DRP1-driven remodeling of select ER microdomains may critically regulate hepatic proteostasis and identify mdivi-1 as a novel small molecule PCSK9 inhibitor.

Translational Perspective: PCSK9 is a critical protein participating in degradation of low-density lipoprotein receptor, a receptor involved in clearance of circulating low-density lipoprotein. Anti-PCSK9 therapies approved for clinical use are currently limited to antibody therapies. PCSK9 siRNA therapy is also showing promise in clinical trials, but small molecule PCSK9 inhibitors have proven difficult to develop. This study identifies a small molecule inhibitor of a mitochondrial fission protein, DRP1 in human hepatocytes and hepatocyte DRP1-deficiency in mice reduces PCSK9 secretion, providing initial proof-of-concept for novel small molecule PCSK9 inhibition.
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http://dx.doi.org/10.1093/cvr/cvab034DOI Listing
February 2021

Porcine epidemic diarrhea virus infections induce autophagy in Vero cells via ROS-dependent endoplasmic reticulum stress through PERK and IRE1 pathways.

Vet Microbiol 2021 Feb 15;253:108959. Epub 2020 Dec 15.

College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, 712100, China. Electronic address:

Porcine epidemic diarrhea virus (PEDV), the causative agent of PED, belongs to the genus Alphacoronavirus in the family Coronaviridae. Reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, and autophagy play crucial roles in regulating a variety of cellular processes during viral infection. However, the precise role of autophagy in PEDV-infected Vero cells remains largely elusive. To elucidate how PEDV infection induces autophagy, this study ascertained whether ER stress was present in PEDV-infected Vero cells. The results showed PEDV infection significantly increased the expression of GRP78 and LC3Ⅱ. Treatment with the ER stress inhibitor 4-phenylbutyrate (4-PBA) could significantly inhibit PEDV-induced autophagy. Antioxidants, such as N-acetylcysteine (NAC), could significantly inhibit PEDV-induced ER stress and autophagy, indicating that ROS act as an upstream regulator of ER stress-mediated autophagy. Further research found that activation of ER stress triggered the unfolded protein response (UPR) through PERK, IRE1, and ATF6 pathways during PEDV infection. However, treatment with the PERK inhibitor GSK2606414, IRE1 inhibitor STF-083010 but not ATF6 inhibitor AEBSF reversed PEDV-induced autophagy. Taken together, the results of this study showed that accumulated ROS played an essential role in regulating ER stress-mediated autophagy during PEDV infection. We also found that PERK and IER1 pathways of UPR signalling were involved in PEDV-induced autophagy. Furthermore, PEDV induced autophagy to promote viral replication via PERK and IER1 pathways in Vero cells. These results provide the mechanism of PEDV-induced ROS-dependent ER stress-mediated autophagy in Vero cells through activating PERK and IRE1 pathways.
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http://dx.doi.org/10.1016/j.vetmic.2020.108959DOI Listing
February 2021

Risk Evaluation for a Manufacturing Process Based on a Directed Weighted Network.

Entropy (Basel) 2020 Jun 23;22(6). Epub 2020 Jun 23.

School of Reliability and Systems Engineering, Beihang University, Beijing 100191, China.

The quality of a manufacturing process can be represented by the complex coupling relationship between quality characteristics, which is defined by the directed weighted network to evaluate the risk of the manufacturing process. A multistage manufacturing process model is established to extract the quality information, and the quality characteristics of each process are mapped to nodes of the network. The mixed embedded partial conditional mutual information (PMIME) is used to analyze the causal effect between quality characteristics, wherein the causal relationships are mapped as the directed edges, while the magnitudes of the causal effects are defined as the weight of edges. The node centrality is measured based on information entropy theory, and the influence of a node is divided into two parts, which are local and indirect effects. Moreover, the entropy value of the directed weighted network is determined according to the weighted average of the centrality of the nodes, and this value is defined as the risk of the manufacturing process. Finally, the method is verified through a public dataset.
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http://dx.doi.org/10.3390/e22060699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517237PMC
June 2020

The Need for Ocular Protection for Health Care Workers During SARS-CoV-2 Outbreak and a Hypothesis for a Potential Personal Protective Equipment.

Front Public Health 2020 12;8:599757. Epub 2020 Nov 12.

Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China.

SARS-CoV-2 is a coronavirus with high infectivity and has caused dramatic pressure on health systems all over the world. Appropriate personal protection for medical staffs is critical. For ocular protection, there is ongoing hot debate and concern for potential ocular transmission of SARS-CoV-2. Ocular manifestations and positive detection of viral RNA in ocular samples were only reported in very small number of patients infected with SARS-CoV-2. However, health care workers need to face patients more closely and have higher risk of aerosol contamination. Thus, appropriate ocular protection for medical workers is still recommended by organizations such as WHO and American Academy of Ophthalmology. Although eye goggles provide excellent protection and are mandatory for medical practitioners with high risk of exposure, they are not ideal for common clinical practice, because they can disturb vision due to extensive formation of water droplets and frequently cause moderate to severe discomfort after longtime wearing, which have been reported to interfere with working status. For the majority of medical workers who don't deal with high risk patients, they are not advised to wear goggles in daily practice. However, they also face the risk of infection due to the presence of asymptomatic carriers. Especially in situations with high risk of ocular exposure, such as close physical examination, eye surgery, dental clinics and surgery, ocular protection may be needed. Griffithsin has been shown to directly bind to spike proteins and has anti-viral activity against a broad spectrum of viruses, including coronavirus. Griffithsin is found to inhibit the entry of SARS-CoV at relatively low concentration and is stable and non-toxic. SARS-CoV-2 and SARS-CoV share the same entry receptors and their spike proteins are similar in conformation. We hypothesize that contact lenses containing nanoparticles loaded with griffithsin may provide sufficient ocular protection for medical staffs without high risk of exposure during the outbreak period of SARS-CoV-2. If proven effective, griffithsin-loaded contact lens can be considered as a supplementary ocular protective equipment for medical workers who can tolerate well. The daily disposable contact lens should be applied as needed and refrain from extended wearing in order to reduce potential side effects.
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http://dx.doi.org/10.3389/fpubh.2020.599757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690622PMC
December 2020

Malassezia species may play potential roles in the pathogenesis of meibomian gland dysfunction.

Med Hypotheses 2020 Nov 26;144:110137. Epub 2020 Jul 26.

Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address:

Meibomian gland dysfunction (MGD) is the most common cause of dry eye disease (DED). Although many factors, such as aging, androgen deficiency, bacterial colonization and drug toxicity have been demonstrated to be associated with MGD, its pathogenesis is not well understood and definite therapies are lacking. Meibomian gland is the largest lipid-secreting gland of human and is the counterpart of sebaceous gland in the eyelid. The lipophilic yeast Malassezia species (spp) habitats in sebaceous gland and is generally considered to play pathogenic roles in seborrheic dermatitis. Several mechanisms have been illuminated, including secretion of lipases, production of toxic metabolites and generation of reactive oxidative species. Anti-fungal therapy is beneficial for patients with seborrheic dermatitis. So far, no previous studies have investigated the link between Malassezia spp and MGD. But there are reports which demonstrate increased prevalence of both high delivery and obstructive MGD in patients with seborrheic dermatitis. Malassezia spp is also found to be associated with anterior blepharitis, the seborrheic inflammation of the other counterpart of sebaceous gland in the eyelid-the Zeis gland. Based on the pathogenic role of Malassezia spp and its highly lipophilic characteristic, we hypothesize that Malassezia spp may also habitat in meibomian gland and play potential pathogenic roles in MGD. Anti-fungal treatment with 2% ketoconazole cream may be potential therapy for patients with MGD. If the hypothesis can be confirmed on patients, it can provide a novel insight of the pathogenesis of MGD and hopefully trigger further investigation into the relationship between microbiota colonization and the function of meibomian gland.
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http://dx.doi.org/10.1016/j.mehy.2020.110137DOI Listing
November 2020

Isomers of B←N-Fused Dibenzo-azaacenes: How B←N Affects Opto-electronic Properties and Device Behaviors?

Chemistry 2021 Mar 3;27(13):4364-4372. Epub 2021 Feb 3.

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Science, 5625 Renmin Rd., Changchun, 130022, China.

The B←N unit has a large dipole and it is isoelectronic to C-C moiety with no dipole. Incorporating B←N units into π-conjugated system is a powerful strategy to design organic small molecules and polymers with intriguing opto-electronic properties and excellent opto-electronic device performance. However, it is unclear how the B←N unit affects electronic structures and opto-electronic properties of large π-conjugated molecules. In this work, to address this question, we developed three dibenzo-azaacene molecules in which two B←N units were introduced at different positions. Although the dibenzo-azaacene skeleton is fully π-conjugated, the effect of B←N unit on the electronic structures of the adjacent rings is much stronger than that of the distant rings. As a result, the three molecules with isomerized B←N incorporation patterns possess different electronic structures and exhibit tunable opto-electronic properties. Among the three molecules, the centrosymmetrical molecule exhibits higher LUMO/HOMO energy levels than those of the two axisymmetrical molecules. When used as the active layer in organic field-effect transistors (OFETs), while the two axisymmetrical molecules show unipolar electron transporting property, the centrosymmetrical molecule exhibits ambipolar hole and electron transporting behavior. This work not only deepens our understanding on organoboron π-conjugated molecules, but also indicates a new strategy to tune opto-electronic properties of organic semiconductors for excellent device performance.
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http://dx.doi.org/10.1002/chem.202004615DOI Listing
March 2021

Vesicular ATP release from hepatocytes plays a role in the progression of nonalcoholic steatohepatitis.

Biochim Biophys Acta Mol Basis Dis 2021 Mar 17;1867(3):166013. Epub 2020 Nov 17.

Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan. Electronic address:

Non-alcoholic steatohepatitis (NASH) is becoming a growing public health problem along with the increase of metabolic syndrome worldwide. Extracellular nucleotides are known to serve as a danger signal by initiating purinergic signaling in many inflammatory disorders, although the role of purinergic signaling in the progression of NASH remains to be clarified. Vesicular nucleotide transporter (VNUT) is a key molecule responsible for vesicular ATP release to initiate purinergic signaling. Here, we studied the role of VNUT in the progression of nonalcoholic steatohepatitis. VNUT was expressed in mouse hepatocytes and associated, at least in part, with apolipoprotein B (apoB)-containing vesicles. High glucose stimulation evoked release of appreciable amount of ATP from hepatocytes, which disappeared in hepatocytes of Vnut knockout (Vnut) mice. Glucose treatment also stimulated triglyceride secretion from hepatocytes, which was inhibited by PPADS and MRS211, antagonists of P2Y receptors, and clodronate, a VNUT inhibitor, and was significantly reduced in Vnut mice. In vivo, postprandial secretion of triglyceride from hepatocytes was observed, while the serum triglyceride level was significantly reduced in Vnut mice. On a high-fat diet, the liver of wild type mice exhibited severe inflammation, fibrosis, and macrophage infiltration, which is similar to NASH in humans, while this NASH pathology was not observed in Vnut mice. These results suggest that VNUT-mediated vesicular ATP release regulates triglyceride secretion and involves in chronic inflammation in hepatocytes. Since blockade of vesicular ATP release protects against progression of steatohepatitis, VNUT may be a pharmacological target for NASH.
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http://dx.doi.org/10.1016/j.bbadis.2020.166013DOI Listing
March 2021

MAVS is energized by Mff which senses mitochondrial metabolism via AMPK for acute antiviral immunity.

Nat Commun 2020 11 11;11(1):5711. Epub 2020 Nov 11.

Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Mitochondria are multifunctional organelles that produce energy and are critical for various signaling pathways. Mitochondrial antiviral signaling (MAVS) is a mitochondrial outer membrane protein essential for the anti-RNA viral immune response, which is regulated by mitochondrial dynamics and energetics; however, the molecular link between mitochondrial metabolism and immunity is unclear. Here we show in cultured mammalian cells that MAVS is activated by mitochondrial fission factor (Mff), which senses mitochondrial energy status. Mff mediates the formation of active MAVS clusters on mitochondria, independent of mitochondrial fission and dynamin-related protein 1. Under mitochondrial dysfunction, Mff is phosphorylated by the cellular energy sensor AMP-activated protein kinase (AMPK), leading to the disorganization of MAVS clusters and repression of the acute antiviral response. Mff also contributes to immune tolerance during chronic infection by disrupting the mitochondrial MAVS clusters. Taken together, Mff has a critical function in MAVS-mediated innate immunity, by sensing mitochondrial energy metabolism via AMPK signaling.
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http://dx.doi.org/10.1038/s41467-020-19287-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658986PMC
November 2020

An Electroactive Pure Organic Room-Temperature Phosphorescence Polymer Based on a Donor-Oxygen-Acceptor Geometry.

Angew Chem Int Ed Engl 2021 Feb 30;60(5):2455-2463. Epub 2020 Nov 30.

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China.

An electroactive room-temperature phosphorescence (RTP) polymer has been demonstrated based on a characteristic donor-oxygen-acceptor geometry. Compared with the donor-acceptor reference, the inserted oxygen atom between donor and acceptor can not only decrease hole-electron orbital overlap to suppress the charge transfer fluorescence, but also strengthen spin-orbital coupling effect to facilitate the intersystem crossing and subsequent phosphorescence channels. As a result, a significant RTP is observed in solid states under photo excitation. Most noticeably, the corresponding polymer light-emitting diodes (PLEDs) reveal a dominant electrophosphorescence with a record-high external quantum efficiency of 9.7 %. The performance goes well beyond the 5 % theoretical limit for typical fluors, opening a new door to the development of pure organic RTP polymers towards efficient PLEDs.
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http://dx.doi.org/10.1002/anie.202011957DOI Listing
February 2021

B←N-Incorporated Dibenzo-azaacene with Selective Near-Infrared Absorption and Visible Transparency.

Chemistry 2021 Jan 22;27(6):2065-2071. Epub 2020 Dec 22.

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China.

Organic compounds with selective near-infrared absorption and visible transparency are very desirable for fabrication of transparent/semitransparent optoelectronic devices. Herein, we develop a molecule with selective near-infrared absorption property, QBNA-O, in which four B←N units are incorporated to the core and two benzodioxin groups are introduced at the termini of the dibenzo-azaacene skeleton. QBNA-O exhibits a small optical gap of 1.39 eV due to the strong electron-donating benzodioxin groups and the strong electron-withdrawing B←N units. In toluene solution, QBNA-O shows a strong absorption peak at 856 nm with the full width at half maximum (FWHM) of only 41 nm as well as very weak absorption in the visible range from 380 nm to 760 nm. Thin films of QBNA-O exhibit the average visible transparency (AVT) of 78 % at the thickness of 205 nm and 90 % at the thickness of 45 nm. Solution-processed organic field-effect transistors (OFETs) of QBNA-O display ambipolar transporting behavior with the electron mobility of 0.52 cm  V  s and the hole mobility of 0.013 cm  V  s together with excellent air-stability. The selective NIR absorbing property and excellent charge transporting property imply that QBNA-O can be used to fabricate transparent organic optoelectronic devices.
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http://dx.doi.org/10.1002/chem.202003925DOI Listing
January 2021

Experimental vascular protective shield combined with vacuum sealing drainage prevents pressure on exposed vessels and accelerates wound repair.

Ann Palliat Med 2020 Sep 20;9(5):3059-3069. Epub 2020 Aug 20.

Research Institute of Orthopedics, the Affiliated Jiangnan Hospital of Zhejiang Chinese Medical University, Hangzhou, China.

Background: The sustained negative pressure created by vacuum sealing drainage (VSD) on exposed vascular wounds can result in blood vessel compression, embolism, or necrosis. The objective of this research was to explore the ability of an experimental vascular protective shield combined with VSD to protect exposed vessels of the lower limbs and accelerate wound repair.

Methods: (I) The vascular protective shield was prepared; (II) the material was subjected to acute toxicity and hemolysis tests; (III) and 30 New Zealand rabbits were divided into three groups: the control, VSD-only, and combined shield-VSD groups (with ten rabbits in each group). The wound-healing rate, myocardial function, wound histopathology, expression of angiogenesis markers, and exposed vascular compression of these three groups were compared on day 7.

Results: (I) The internal structure of the material was smooth; and (II) no toxicity or death was observed in mice of any group. The hemolysis rate in the combined shield-VSD group was very low. (III) The combined shield-VSD group showed a higher wound-healing rate, and higher levels of cluster of differentiation 31 (CD31), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF), than the other groups (P<0.05), along with a better tissue healing rate. (IV) Left ventricular pressure fluctuations in the combined shield-VSD group were smaller than those in the VSD-only group (P<0.05). (V) Blood vessels in the control and combined shield-VSD group were not damaged, but were damaged in the VSD-only group.

Conclusions: The experimental vascular protective shield exhibited exceptional biosafety. The combination of this shield with VSD reduces influences on systolic and diastolic capacities of myocardium and avoids multiple compressions of exposed vessels, thus contributing to early vascularization of wounds and wound repair.
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http://dx.doi.org/10.21037/apm-20-625DOI Listing
September 2020

The applications of androgen in the treatment of dry eye disease: a systematic review of clinical studies.

Endocr J 2020 Sep 18;67(9):893-902. Epub 2020 Aug 18.

Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.

Androgen regulates the function of lacrimal and meibomian glands, and its deficiency is a pathological factor underlying dry eye disease (DED). However, no androgen has been approved for treating DED due to lack of definite evidence regarding its efficacy and safety in clinics. In this systematic review, we have summarized the clinical studies on the safety and efficacy of androgen replacement therapy (ART) for DED. Medline (via Pubmed), Embase, Clinicaltrials.gov, Wanfang and Chinese Clinical Trials Registry Database were searched for the relevant prospective studies, and 7 studies wherein androgen was applied topically via eye drops or systemically via oral or transdermal administration were included. The quality of these studies was assessed with the Cochrane Collaboration's tool for assessing risk of bias and methodological index for non-randomized studies. Most studies showed that androgen effectively improved dry eye-related symptoms and increased tear secretion. Furthermore, elderly men and peri-menopausal women with lower levels of circulating androgens responded better to ART. However, one study involving patients with Sjögren's syndrome showed no improvement in the ART group compared to the placebo control, or to the baseline level. Adverse effects were also common but limited to mild skin problems. In conclusion, androgen is a potential treatment for dry eye disease, especially for people with primary androgen deficiency. Short-term application is relatively safe.
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http://dx.doi.org/10.1507/endocrj.EJ20-0178DOI Listing
September 2020

Panchromatic Organoboron Molecules with Tunable Absorption Spectra.

Chem Asian J 2020 Oct 14;15(20):3314-3320. Epub 2020 Sep 14.

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China.

Panchromatic molecules, e. g. organic small molecules with wide absorption spectra, are very desirable for solar energy-related applications. Here, we report the development of a series of organoboron compounds composed of an organoboron core unit, two π-bridging units and two electron-withdrawing end-capping units. All seven molecules have the HOMO localized on the core unit and the LUMO delocalized on the whole conjugated backbone. They exhibit wide absorption spectra consisting of two strong absorption bands with the full width at half maximum of ca. 280 nm. These panchromatic compounds can be used as electron acceptors in organic solar cells. We elucidate the relationship between the chemical structures and opto-electronic properties of these organoboron panchromatic compounds. Increasing the electron-withdrawing capability of the core units results in a downshifted HOMO level as well as blueshifted long-wavelength absorption band with increased extinction coefficient. Extending the π-bridging units causes an increased HOMO level and blueshifted long-wavelength absorption band with increased extinction coefficients. Weakening the electron-withdrawing capability of the end-capping units leads to an upshifted LUMO level and blueshifted long-wavelength absorption peak with decreased extinction coefficient. This work provides insight into the absorption spectrum manipulation of panchromatic molecules and would pave the way for the development of solar energy-related applications.
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http://dx.doi.org/10.1002/asia.202000958DOI Listing
October 2020

Through-Space Charge-Transfer Polynorbornenes with Fixed and Controllable Spatial Alignment of Donor and Acceptor for High-Efficiency Blue Thermally Activated Delayed Fluorescence.

Angew Chem Int Ed Engl 2020 Nov 28;59(45):20174-20182. Epub 2020 Aug 28.

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun Jilin, 130022, P. R. China.

Through-space charge transfer polynorbornenes with fixed and controllable spatial alignment of donor and acceptor in edge-to-face/face-to-face stacking patterns are developed for achieving high-efficiency blue thermally activated delayed fluorescence (TADF). The alignment is realized by using the cis, exo-configuration of norbornene to confine donor and acceptor in close proximity, and utilizing orthogonal and dendritic structures of donors to provide either perpendicular or parallel stacking motif relative to acceptors. Compared to edge-to-face counterparts, polynorbornenes with face-to-face aligned donor and acceptor exhibit much larger oscillator strength and higher photoluminescence quantum yield. The resulting polymers exhibit deep blue (422 nm) to sky blue (482 nm) emission and TADF effect with reverse intersystem crossing rates of 0.4-5.9×10  s , giving the maximum external quantum efficiency of 18.8 % for non-doped blue organic light-emitting diodes by solution process.
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http://dx.doi.org/10.1002/anie.202008912DOI Listing
November 2020

Polymer Acceptors Containing B←N Units for Organic Photovoltaics.

Acc Chem Res 2020 Aug 21;53(8):1557-1567. Epub 2020 Jul 21.

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China.

ConspectusOrganic photovoltaics (OPVs), in which blend films of organic or polymer electron donor and electron acceptor are used as the active layer, are a promising photovoltaic technology with the great advantages of solution processing, low cost, and flexibility. The development of small molecular or polymer electron acceptors has boosted power conversion efficiency (PCE) of OPVs from 10% to 18%. Among them, polymer acceptors have the merits of superior morphology stability and excellent mechanical properties. However, owing to the key requirement of very low-lying LUMO/HOMO energy levels for polymer acceptors, very few conjugated polymers can work as polymer acceptors in OPVs. The majority of polymer electron acceptors are based on strong electron-withdrawing imide units or cyano substituents. Since 2015, conjugated polymers containing the boron-nitrogen coordination bond (B←N) have emerged as a new kind of polymer electron acceptor with excellent photovoltaic performance in various kinds of organic photovoltaic devices. In this Account, we summarize our research progress on polymer acceptors containing B←N units.At first, we introduce the principle of B←N to greatly down shift LUMO/HOMO energy levels, which enables B←N to be used to design polymer acceptors. Then we describe the two molecular design strategies for polymer acceptors containing B←N units. For high-efficiency OPVs, polymer acceptors should have wide absorption spectra, proper LUMO/HOMO energy levels, high electron mobility, and good donor/acceptor blend morphology. We discuss how to use molecular design to finely tune the absorption spectra, energy levels, and electron mobility of the B←N-containing polymer acceptors. We also discuss how to improve the phase separation morphology of the blends of these polymer acceptors with small molecular donors or polymer donors. These improvements lead to excellent performance of the polymer acceptors containing B←N units in three kinds of organic photovoltaic devices. The small molecular donor/polymer acceptor type organic solar cells show excellent thermal stability and PCE of 8.0%, which is the highest value reported so far. The all-polymer solar cells exhibit PCE of 10.1%. The all-polymer indoor photovoltaics show PCE as high as 27.4% under fluorescent lamp illumination at 2000 lx. This PCE is fairly comparable to those of the best organic or inorganic indoor photovoltaics. These results provide a solid foundation for future advances. Finally, we propose that great attention should be paid to further PCE enhancement of OPVs and indoor photovoltaic applications of this new emerging kind of polymer acceptor.
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http://dx.doi.org/10.1021/acs.accounts.0c00281DOI Listing
August 2020