Publications by authors named "Lu Lu"

1,441 Publications

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Long-acting Protective Ocular Surface by Instilling Adhesive Dual-antiviral Nanoparticles.

Adv Healthc Mater 2022 May 17:e2200283. Epub 2022 May 17.

Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Department of Ophthalmology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200011, P. R. China.

The eye is susceptible to viral infections, causing severe ocular symptoms or even respiratory diseases. Methods capable of protecting the eye from external viral invasion in a long-term and highly effective way are urgently needed but have been proved to be extremely challenging. Here, a strategy of forming long-acting protective ocular surface is described by instilling adhesive dual-antiviral nanoparticles. Taking pseudotyped severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a model virus, antiviral agent-loaded nanoparticles are coated with a "double-lock" hybrid cell membrane abundant with integrin-β1 and angiotensin converting enzyme II (ACE2). After instillation, the presence of integrin-β1 endows coated nanoparticles with steady adhesion via specific binding to Arg-Gly-Asp sequence on the fibronectin of ocular epithelium, achieving durable retention on ocular surface. In addition to loaded inhibitors, the exposure of ACE2 can trap SARS-CoV-2 and subsequently neutralize the associated spike protein, playing a dual antiviral effect of the resulting nanoparticles. Adhesive dual-antiviral nanoparticles enabled by coating with a "double-lock" hybrid cell membrane propose a versatile platform for topical long-acting protection against viral infection of the eye. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/adhm.202200283DOI Listing
May 2022

The Application of Anatomy Combined With Ultrasound Knife in Transaxillary Endoscopic Biplane Breast Augmentation.

Front Surg 2022 27;9:865379. Epub 2022 Apr 27.

Department of Plastic and Reconstructive Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.

Objective: We aim to clarify the vascular and nerve anatomy of the breast and combine it with an ultrasound knife to use in transaxillary endoscopic biplane breast augmentation.

Methods: This study is a retrospective review of patients undergoing transaxillary endoscopic biplane breast augmentation between October and October 2021. Related variables were collected using a standardized data collection template. The detailed process of the transaxillary endoscopic biplane breast augmentation under anatomy instruction is carefully described in this study, and the postoperative effect was closely observed.

Results: Sixty-three female patients underwent transaxillary endoscopic biplane breast augmentation. The average implants volume counted 242.46 ± 31.34 cc, and the average operation time was 155.92 ± 22.34 min. Patients were followed up for a mean of 13.67 months (range, 3-27 months), and most of the patients achieved good postoperative results and no severe complications and were satisfied with both appearance and function.

Conclusions: The application of anatomy combined with an ultrasound knife in transaxillary endoscopic biplane breast augmentation is a promising way to achieve good breast shapes with high patient satisfaction and is worthy of clinical promotion and application.
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http://dx.doi.org/10.3389/fsurg.2022.865379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9091814PMC
April 2022

Magnesium oxide nanotube as a promising material for detection of methamphetamine drug: theoretical study.

J Mol Model 2022 May 14;28(6):150. Epub 2022 May 14.

College of Pharmacy, Jiangsu Health Vocational College, Nanjing, 211800, China.

Owing to the negative impacts of abusing illegal drugs like methamphetamine (MAF), their detection and control are of paramount importance. Therefore, it is very critical to determine MAF in biological samples. The current research study investigated the sensing interaction of inherent and MgO nanotubes (MgONT) toward MAF via density functional theory computations. We determined that the MgONT has a sensing response of 283.31, and it remarkably improves the reactivity toward MAF. The levels of energy for the highest occupied and the lowest unoccupied molecular orbitals have changed to a great extent, thereby reducing bandgap (E) values which increased electrical conductivity. Furthermore, a short recovery time (~ 28.65 ms) has been anticipated for MAF desorption from the MgONT exterior. This piece of research showed that MgONT might be a possible electronic sensor and an appropriate choice to deliver MAF in biological samples.
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http://dx.doi.org/10.1007/s00894-022-05151-6DOI Listing
May 2022

PyLiger: scalable single-cell multi-omic data integration in Python.

Bioinformatics 2022 May;38(10):2946-2948

Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.

Motivation: LIGER (Linked Inference of Genomic Experimental Relationships) is a widely used R package for single-cell multi-omic data integration. However, many users prefer to analyze their single-cell datasets in Python, which offers an attractive syntax and highly optimized scientific computing libraries for increased efficiency.

Results: We developed PyLiger, a Python package for integrating single-cell multi-omic datasets. PyLiger offers faster performance than the previous R implementation (2-5× speedup), interoperability with AnnData format, flexible on-disk or in-memory analysis capability and new functionality for gene ontology enrichment analysis. The on-disk capability enables analysis of arbitrarily large single-cell datasets using fixed memory.

Availability And Implementation: PyLiger is available on Github at https://github.com/welch-lab/pyliger and on the Python Package Index.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btac190DOI Listing
May 2022

Polymer chimera of stapled oncolytic peptide coupled with anti-PD-L1 peptide boosts immunotherapy of colorectal cancer.

Theranostics 2022 24;12(7):3456-3473. Epub 2022 Apr 24.

Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.

Scarce tumor mutation burden and neoantigens create tremendous obstacles for an effective immunotherapy of colorectal cancer (CRC). Oncolytic peptides rise as a promising therapeutic approach that boosts tumor-specific immune responses by inducing antigenic substances. However, the clinical application of oncolytic peptides has been hindered because of structural instability, proteolytic degradation, and undesired toxicity when administered systemically. Based on wasp venom peptide, an optimized stapled oncolytic peptide MP9 was developed with rigid α-helix, protease-resistance, and CRC cell cytotoxicity. By incorporating four functional motifs that include D-peptidomimetic inhibitor of PD-L1, matrix metalloproteinase-2 (MMP-2) cleavable spacer, and MP9 with 4-arm PEG, a novel peptide-polymer conjugate (PEG-MP9-aPDL1) was obtained and identified as the most promising systemic delivery vehicle with PD-L1 targeting specificity and favorable pharmacokinetic properties. We demonstrated that PEG-MP9-aPDL1-driven oncolysis induces a panel of immunogenic cell death (ICD)-relevant damage-associated molecular patterns (DAMPs) both and , which are key elements for immunotherapy with PD-L1 inhibitor. Further, PEG-MP9-aPDL1 exhibited prominent immunotherapeutic efficacy in a CRC mouse model characterized by tumor infiltration of CD8+ T cells and induction of cytotoxic lymphocytes (CTLs) in the spleens. Our findings suggest that PEG-MP9-aPDL1 is an all-in-one platform for oncolytic immunotherapy and immune checkpoint blockade (ICB).
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http://dx.doi.org/10.7150/thno.71129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9065177PMC
May 2022

A natural mutator allele shapes mutation spectrum variation in mice.

Nature 2022 May 11. Epub 2022 May 11.

Department of Genome Sciences, University of Washington, Seattle, WA, USA.

Although germline mutation rates and spectra can vary within and between species, common genetic modifiers of the mutation rate have not been identified in nature. Here we searched for loci that influence germline mutagenesis using a uniquely powerful resource: a panel of recombinant inbred mouse lines known as the BXD, descended from the laboratory strains C57BL/6J (B haplotype) and DBA/2J (D haplotype). Each BXD lineage has been maintained by brother-sister mating in the near absence of natural selection, accumulating de novo mutations for up to 50 years on a known genetic background that is a unique linear mosaic of B and D haplotypes. We show that mice inheriting D haplotypes at a quantitative trait locus on chromosome 4 accumulate C>A germline mutations at a 50% higher rate than those inheriting B haplotypes, primarily owing to the activity of a C>A-dominated mutational signature known as SBS18. The B and D quantitative trait locus haplotypes encode different alleles of Mutyh, a DNA repair gene that underlies the heritable cancer predisposition syndrome that causes colorectal tumors with a high SBS18 mutation load. Both B and D Mutyh alleles are present in wild populations of Mus musculus domesticus, providing evidence that common genetic variation modulates germline mutagenesis in a model mammalian species.
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http://dx.doi.org/10.1038/s41586-022-04701-5DOI Listing
May 2022

Genetic dissection of glutathione S-transferase omega-1: identification of novel downstream targets and Alzheimer's disease pathways.

Neural Regen Res 2022 Nov;17(11):2452-2458

Department of Histology and Embryology, Medical College, Nantong University; Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China.

Alzheimer's disease (AD) is affected by genetic factors. Polymorphisms in the glutathione S-transferase omega-1 (Gsto1) gene have been shown by genetic correlation analyses performed in different ethnic populations to be genetic risk factors for AD. Gene expression profile data from BXD recombinant inbred mice were used in combination with genetic and bioinformatic analyses to characterize the mechanisms underlying regulation of Gsto1 variation regulation and to identify network members that may contribute to AD risk or progression. Allele-specific assays confirmed that variation in Gsto1 expression is controlled by cis-expression quantitative trait loci. We found that Gsto1 mRNA levels were related to several central nervous system traits, such as glial acidic fibrillary protein levels in the caudate putamen, cortical gray matter volume, and hippocampus mossy fiber pathway volume. We identified 2168 genes whose expression was highly correlated with that of Gsto1. Some genes were enriched for the most common neurodegenerative diseases. Some Gsto1-related genes identified in this study had previously been identified as susceptibility genes for AD, such as APP, Grin2b, Ide, and Psenen. To evaluate the relationships between Gsto1 and candidate network members, we transfected astrocytes with Gsto1 siRNA and assessed the effect on putative downstream effectors. We confirmed that knockdown of Gsto1 had a significant influence on Pa2g4 expression, suggesting that Pa2g4 may be a downstream effector of Gsto1, and that both genes interact with other genes in a network during AD pathogenesis.
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http://dx.doi.org/10.4103/1673-5374.339004DOI Listing
November 2022

[Chinese medicine dispensing granules: history, status quo, and development prospect in "post-pilot era"].

Zhongguo Zhong Yao Za Zhi 2022 Apr;47(8):2008-2014

Department of Pharmacy,the First Affiliated Hospital of Henan University of Chinese Medicine Zhengzhou 450000, China Henan Engineering Research Center for Modernization of Clinical Application of Chinese Herbal Pieces Zhengzhou 450000, China Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases Co-constructed by Henan Province and Education Ministry,Henan University of Chinese Medicine Zhengzhou 450046, China Henan Key Laboratory for Clinical Pharmacy of Traditional Chinese Medicine Zhengzhou 450000, China.

Chinese medicine dispensing granules, the result of the efforts to transform Chinese medicinal decoction pieces in China, features portability and ease of storage. Thus, it is destined to be an indispensible dosage form in the modernization drive of Chinese medicine. The Announcement on Ending the Pilot Project of Chinese Medicine Dispensing Granules was released in February 2021 and relevant regulations went into force in November 2021, which marks the a new journey for the development of Chinese medicine dispensing granules and the beginning of the "post-pilot era". However, it faces the challenges in quality and standard. This study reviewed the history of Chinese medicine dispensing granules, analyzed the technical progress, market, and main problems in development, and proposed suggestions and prospects for its development in the "post-pilot era", which is expected to serve as a reference for its industry development and rational use.
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http://dx.doi.org/10.19540/j.cnki.cjcmm.20211111.601DOI Listing
April 2022

Advances in the Pharmacological Intervention of Endothelial Progenitor Cells in the Treatment of Ischemic Stroke.

Cerebrovasc Dis 2022 May 5:1-9. Epub 2022 May 5.

Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China.

Background: Ischemic stroke, a common central nervous system disease that seriously threatens human life and health, is characterized by rapid progress and a high disability fatality rate. Ischemic tissue can produce a large amount of vascular endothelial growth factor (VEGF) and stromal cell-derived factor 1 (SDF-1) to promote the mobilization of endothelial progenitor cells (EPCs).

Summary: As newly discovered stem cells, EPCs can promote angiogenesis in ischemic tissue, repair the damaged vascular endothelium, and maintain vascular homeostasis. Thus, EPCs have become a new research hotspot in this field. This review focuses on the mechanism of EPCs and the intervention of various novel drugs, including small molecules and biomolecules, which will promote the capture, proliferation, and differentiation of EPCs. Then, we explore the promotion of vascular health and the prospect of its application in the treatment of cerebral ischemic stroke (CIS).

Key Message: It is clinically significant to study the potential of new drug therapy to target EPCs. More effective cytokines, signal pathways, and other drugs should be explored in the future and their specific mechanisms determined. Research should reveal more biological functions of EPCs and achieve their efficient amplification to improve therapy against CIS stroke.
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http://dx.doi.org/10.1159/000524414DOI Listing
May 2022

Comparison of structural and functional properties of maize starch produced with commercial or endogenous enzymes.

Int J Biol Macromol 2022 Jun 30;209(Pt B):2213-2225. Epub 2022 Apr 30.

State Key Laboratory of Biobased Material and Green Papermaking, School of Food Sciences and Engineering, Qilu University of Technology, Shandong Academy of Sciences, Jinan, China.

To explore an effective and economic method to prepare higher contents of resistant starch (RS), different enzyme treatments including single pullulanase (PUL), commercial α-amylase (AA) or/and β-amylase (BA) with PUL, and malt endogenous amylase (MA) with PUL were used and the structural, physicochemical properties and digestibility of all modified starches (MS) were compared. All the enzyme-treated starches displayed a mixture of B and V-type diffraction patterns. The MA/PUL-MS showed higher V-type diffraction peak intensity as compared to other modified starches. Compared to the combination of commercial enzyme treatment, the combination of malt enzyme treatment led to higher apparent amylose contents (45.56%), RS content (53.93%) and thermal stability (302 °C), whereas it possessed lower solubility indices and predicted glycaemic index. The apparent viscosity and shear resistance of MA/PUL-MS were lower than that of AA/PUL-MS, whereas that of MA/PUL-MS was higher than that of BA/PUL-MS and BA/AA/PUL-MS. These findings would provide a theoretical and applicative basis to produce foods with lower GI in industrial production.
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http://dx.doi.org/10.1016/j.ijbiomac.2022.04.202DOI Listing
June 2022

Dual-Cross-linked Liquid Crystal Hydrogels with Controllable Viscoelasticity for Regulating Cell Behaviors.

ACS Appl Mater Interfaces 2022 May 3;14(19):21966-21977. Epub 2022 May 3.

Biomaterial Research Laboratory, Department of Material Science and Engineering, College of Chemistry and Materials, Jinan University, Guangzhou 510632, P. R. China.

The liquid crystal properties and viscoelasticity of the natural bone extracellular matrix (ECM) play a decisive role in guiding cell behavior, conducting cell signals, and regulating mineralization. Here, we develop a facile approach for preparing a novel polysaccharide hydrogel with liquid crystal properties and viscoelasticity similar to those of natural bone ECM. First, a series of chitin whisker/chitosan (CHW/CS) hydrogels were prepared by chemical cross-linking with genipin, in which CHW can self-assemble to form cholesteric liquid crystals under ultrasonic treatment and CS chains can enter into the gaps between the helical layers of the CHW cholesteric liquid crystal phase to endow morphological stability and good mechanical properties. Subsequently, the obtained chemically cross-linked liquid crystal hydrogels were immersed into the desired concentration of the NaCl solution to form physical cross-linking. Due to the Hofmeister effect, the as-prepared dual-cross-linked liquid crystal hydrogels showed an enhanced modulus, viscoelasticity similar to that of natural ECM with relatively fast stress relaxation behavior, and fold surface morphology. Compared to both CHW/CS hydrogels without liquid crystal properties and CHW/CS liquid crystal hydrogels without further physical cross-linking, the dual-cross-linked CHW/CS liquid crystal hydrogels are more favorable for the adhesion, proliferation, and osteogenic differentiation of bone marrow mesenchymal stem cells. This approach could inspire the design of hydrogels mimicking the liquid crystal properties and viscoelasticity of natural bone ECM for bone repair.
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http://dx.doi.org/10.1021/acsami.2c02689DOI Listing
May 2022

(-)-5-O-(3-O-β-d-Glucopyranosylcaffeoyl)-quinic acid from the fruits of Lycium barbarum L. var. auranticarpum K. F. Ching: Purification, identification and in vitro bioactivities.

Food Chem 2022 Apr 25;389:133081. Epub 2022 Apr 25.

Institute of Wolfberry Engineering Technology, Ningxia Academy of Agriculture and Forestry Sciences, Yinchuan 750002, Ningxia, China; National Wolfberry Engineering Research Center, Yinchuan 750002, Ningxia, China. Electronic address:

Chlorogenic acids are important phenolics in the fruits of wolfberry, but little attention has been paid on their glucosylated forms. In the present study, a glucosylated form of chlorogenic acid was isolated from the fruits of Lycium barbarum L. var. auranticarpum K. F. Ching (also called yellow wolfberry) and identified to be (-)-5-O-(3-O-β-d-glucopyranosylcaffeoyl)-quinic acid (5-CQA-3'βG) by high resolution mass spectrometry and nuclear magnetic resonance spectrometry. The content of 5-CQA-3'βG in the dried fruit was determined as 0.0293 ± 0.0015% by HPLC. In addition, 5-CQA-3'βG showed a good scavenging capacity for 2,2'-azino-bis-(3-ethylben-zothiazoline-6-sulphonate) free radicals but had a relatively low reducing power and scavenging capacity for 2,2-diphenyl-1-picrylhydrazyl free radical. Moreover, the secretion of nitric oxide, tumor necrosis factor-α and interleukin-6 as well as related mRNA expression were reduced in lipopolysaccharide-stimulated RAW264.7 macrophage cells treated with 5-CQA-3'βG. This is the first report describing purification, identification and bioactivity of glucosylated CQA from yellow wolfberry.
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http://dx.doi.org/10.1016/j.foodchem.2022.133081DOI Listing
April 2022

Injectable multifunctional hyaluronic acid/methylcellulose hydrogels for chronic wounds repairing.

Carbohydr Polym 2022 Aug 4;289:119456. Epub 2022 Apr 4.

National Engineering Research Center for Biomaterials, Chuanda-Jinbo Joint Research Center, Sichuan University, Chengdu, 610064, China. Electronic address:

Herein, an injectable multifunctional hydrogel based on dopamine grafted hyaluronic acid and phenylboric acid grafted methylcellulose was fabricated for promoting the repair of diabetic wounds. The prepared hydrogel possessed multifunctional properties including rapid gelation time (less than 10 s), self-healing, high water absorbency, tissue adhesiveness and excellent antioxidant activity. After loading Ag nanoparticles and the recombinant humanized collagen type III with high affinity to cells, the hydrogel exhibited properties of pH-/HO-responsive drug release profile, promoting cell proliferation and ideal antibacterial activity. Moreover, the in vivo experimental results demonstrated the prepared hydrogel could significantly accelerate wound repair by enhancing the collagen deposition and granulation tissue regeneration, reducing the expression of CD68 and improving the production of Ki67 and CD31 simultaneously. In conclusion, these multifunctional injectable hydrogels possessed great potential in chronic wound dressings.
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http://dx.doi.org/10.1016/j.carbpol.2022.119456DOI Listing
August 2022

circ_CSNK1E modulates airway smooth muscle cells proliferation and migration via miR-34a-5p/VAMP2 axis in asthma.

Cell Signal 2022 Apr 26;95:110340. Epub 2022 Apr 26.

Department of Pediatrics, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, No.321. Zhongshan Road, 210008 Nanjing, Jiangsu, China. Electronic address:

Background: Excessive proliferation and migration of airway smooth muscle cells (ASMCs) directly lead to airway remodeling in asthma. However, the role of circular RNAs (circRNAs) in airway remodeling remains unclear. This study aimed to investigate the regulatory role and mechanism of circ_CSNK1E in ASMCs proliferation and migration.

Methods: In this study, RNA-sequencing was used to analyze cicRNAs expression in asthma samples. ASMCs were treated with 25 ng/ml PDGF-BB to establish a model of asthma in vitro. Then, we used RT-qPCR to assess circRNAs, microRNAs (miRNAs) and messenger RNAs (mRNAs) expression. Besides, CCK-8, colony formation, wound healing and transwell chamber assays were carried out to explore cell proliferation and migration. Subcellular localization assay was used to detect the location of circRNA. Next, bioinformatics, luciferase reporter and RIP assays were performed to evaluate the relationship among circ_CSNK1E, miRNA-34a-5p and VAMP2.

Results: circ_CSNK1E expression was found to be significantly up-regulated in asthma samples and PDGF-BB-induced ASMCs. Functional experiments revealed that inhibition of circRNA_CSNK1E suppressed proliferation and migration of ASMCs stimulated by PDGF-BB. Next, we found that circRNA_CSNK1E served as a sponge for miR-34a-5p in ASMCs, and miR-34a-5p mimic suppressed proliferation and migration of ASMCs. Moreover, VAMP2 was confirmed as a direct target of miR-34a-5p. At last, inhibition of circRNA_CSNK1E suppressed proliferation and migration of ASMCs stimulated by PDGF-BB through miR-34a-5p/VAMP2 axis.

Conclusion: Collectively, these findings clarified the importance of circ_CSNK1E/miRNA-34a-5p/VAMP2 axis for the proliferation and migration of ASMCs. These indicated that inhibition of circ_CSNK1E might be a potential target for the treatment of airway remodeling in asthma.
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http://dx.doi.org/10.1016/j.cellsig.2022.110340DOI Listing
April 2022

Erratum to "Resveratrol prevents TNF-α-induced muscle atrophy via regulation of Akt/mTOR/FoxO1 signaling in C2C12 myotubes" [Int. Immunopharmacol. 19 (2014) 206-213].

Int Immunopharmacol 2022 Jun 21;107:108776. Epub 2022 Apr 21.

Nephropathy Center of Integrated Traditional Chinese Medicine and Western Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China; School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China; Division of Nephrology, TCM-Integrated Hospital, Southern Medical University, Guangzhou 510280, China. Electronic address:

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http://dx.doi.org/10.1016/j.intimp.2022.108776DOI Listing
June 2022

The combination of PD-1 blockade with interferon-α has a synergistic effect on hepatocellular carcinoma.

Cell Mol Immunol 2022 Apr 22. Epub 2022 Apr 22.

Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China.

Background: The efficacy of immune checkpoint inhibitors (ICIs), such as programmed cell death protein-1 (PD-1) or its ligand 1 (PD-L1) antibody, in hepatocellular carcinoma (HCC) is limited, and it is recommended that they be combined with other therapies. We evaluated the combination of pegylated interferon-α (Peg-IFNα) with PD-1 blockade in HCC mouse models.

Methods: We analyzed the effects of Peg-IFNα on tumor-infiltrating immune cells and PD-1 expression in the HCC immune microenvironment and examined the underlying mechanism of its unique effect on the PD-1 pathway. The in vivo efficacy of anti-PD-1 and Peg-IFNα was evaluated in both subcutaneous and orthotopic mouse models of HCC.

Results: The combination of Peg-IFNα with PD-1 blockade dramatically enhanced T-cell infiltration, improved the efficacy of PD-1 antibody and prolonged mouse survival compared with PD-1 antibody monotherapy. Mechanistically, Peg-IFNα could recruit cytotoxic CD8 T cells to infiltrate the HCC microenvironment by inducing tumor cells to secrete the chemokine CCL4. Nevertheless, the HCC microenvironment quickly overcame the immune responses by upregulating PD-1 expression in CD8 T cells via the IFNα-IFNAR1-JAK1-STAT3 signaling pathway. The combination of PD-1 blockade with Peg-IFNα could restore the cytotoxic capacity of CD8 T cells and exerted a significant synergistic effect on HCC.

Conclusion: These results indicate that in addition to initiating the antitumor immune response itself, Peg-IFNα can also generate a microenvironment favoring PD-1 blockade. Thus, the combination of Peg-IFNα and PD-1 blockade can be a promising strategy for HCC.
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http://dx.doi.org/10.1038/s41423-022-00848-3DOI Listing
April 2022

A Modified Fibronectin Type III Domain-Conjugated, Long-Acting Pan-Coronavirus Fusion Inhibitor with Extended Half-Life.

Viruses 2022 Mar 22;14(4). Epub 2022 Mar 22.

Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai 200032, China.

The coronavirus disease 2019 (COVID-19) pandemic caused by infection of SARS-CoV-2 and its variants has posed serious threats to global public health, thus calling for the development of potent and broad-spectrum antivirals. We previously designed and developed a peptide-based pan-coronavirus (CoV) fusion inhibitor, EK1, which is effective against all human CoVs (HCoV) tested by targeting the HCoV S protein HR1 domain. However, its relatively short half-life may limit its clinical use. Therefore, we designed, constructed, and expressed a recombinant protein, FL-EK1, which consists of a modified fibronectin type III domain (FN3) with albumin-binding capacity, a flexible linker, and EK1. As with EK1, we found that FL-EK1 could also effectively inhibit infection of SARS-CoV-2 and its variants, as well as HCoV-OC43. Furthermore, it protected mice from infection by the SARS-CoV-2 Delta variant and HCoV-OC43. Importantly, the half-life of FL-EK1 (30 h) is about 15.7-fold longer than that of EK1 (1.8 h). These results suggest that FL-EK1 is a promising candidate for the development of a pan-CoV fusion inhibitor-based long-acting antiviral drug for preventing and treating infection by current and future SARS-CoV-2 variants, as well as other HCoVs.
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http://dx.doi.org/10.3390/v14040655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9028128PMC
March 2022

A Protein-Based, Long-Acting HIV-1 Fusion Inhibitor with an Improved Pharmacokinetic Profile.

Pharmaceuticals (Basel) 2022 Mar 30;15(4). Epub 2022 Mar 30.

Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai 200032, China.

Recently, a series of highly effective peptide- or protein-based HIV fusion inhibitors have been identified. However, due to their short half-life, their clinical application is limited. Therefore, the development of long-acting HIV fusion inhibitors is urgently needed. Here, we designed and constructed a protein-based, long-acting HIV fusion inhibitor, termed FLT (FN3-L35-T1144), consisting of a monobody, FN3, which contains an albumin-binding domain (ABD), a 35-mer linker (L35), and a peptide-based HIV fusion inhibitor, T1144. We found that FLT bound, via its FN3 component, with human serum albumin (HSA) in a reversible manner, thus maintaining the high efficiency of T1144 against infection by both HIV-1 IIIB (X4) and Bal (R5) strains with IC of 11.6 nM and 15.3 nM, respectively, and remarkably prolonging the half-life of T1144 (~27 h in SD rats). This approach affords protein-based HIV fusion inhibitors with much longer half-life compared to enfuvirtide, a peptide-based HIV fusion inhibitor approved for use in clinics. Therefore, FLT is a promising candidate as a new protein-based anti-HIV drug with an improved pharmacokinetic profile.
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http://dx.doi.org/10.3390/ph15040424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9025429PMC
March 2022

Progress on SARS-CoV-2 3CLpro Inhibitors: Inspiration from SARS-CoV 3CLpro Peptidomimetics and Small-Molecule Anti-Inflammatory Compounds.

Drug Des Devel Ther 2022 8;16:1067-1082. Epub 2022 Apr 8.

Shulan International Medical College, Zhejiang Shuren University, Hangzhou, People's Republic of China.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) currently poses a threat to human health. 3C-like proteinase (3CLpro) plays an important role in the viral life cycle. Hence, it is considered an attractive antiviral target protein. Whole-genome sequencing showed that the sequence homology between SARS-CoV-2 3CLpro and SARS-CoV 3CLpro is 96.08%, with high similarity in the substrate-binding region. Thus, assessing peptidomimetic inhibitors of SARS-CoV 3CLpro could accelerate the development of peptidomimetic inhibitors for SARS-CoV-2 3CLpro. Accordingly, we herein discuss progress on SARS-CoV-2 3CLpro peptidomimetic inhibitors. Inflammation plays a major role in the pathophysiological process of COVID-19. Small-molecule compounds targeting 3CLpro with both antiviral and anti-inflammatory effects are also briefly discussed in this paper.
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http://dx.doi.org/10.2147/DDDT.S359009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9015912PMC
April 2022

Design, Synthesis, and Evaluation of PD-1/PD-L1 Antagonists Bearing a Benzamide Scaffold.

ACS Med Chem Lett 2022 Apr 29;13(4):586-592. Epub 2022 Mar 29.

State Key Laboratory of Natural Medicines, Department of Medicinal Chemistry and Department of Biomedical Engineering, China Pharmaceutical University, Nanjing 210009, China.

Several antibodies targeting programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) have been approved by the U.S. Food and Drug Administration (FDA) for cancer therapy. Although many small-molecule inhibitors of the PD-1/PD-L1 pathway have been reported, no small-molecule inhibitors have been approved for cancer treatment. In this work, a series of novel benzamide derivatives were designed, synthesized, and evaluated to find effective inhibitors of the PD-1/PD-L1 interaction. The most potent compound exhibited better activity than that of BMS202, with an IC of 16.17 nM. could activate the antitumor immunity of T cells efficiently in PBMCs. The proposed binding mode of compound was investigated by docking analysis. These results indicate that compound is a promising lead compound that can be used for further development.
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http://dx.doi.org/10.1021/acsmedchemlett.1c00646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9014519PMC
April 2022

Nuanxinkang protects against ischemia/reperfusion-induced heart failure through regulating IKKβ/IκBα/NF-κB-mediated macrophage polarization.

Phytomedicine 2022 Jul 30;101:154093. Epub 2022 Mar 30.

The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510405, PR China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, PR China; Guangzhou Key Laboratory of Chinese Medicine for Prevention and Treatment of Chronic Heart Failure, Guangzhou 510405, PR China. Electronic address:

Background: Heart failure (HF) is a leading cause of death worldwide. Nuanxinkang (NXK) is an effective Chinese herbal formula used in treating HF, but its underlying potential mechanisms have not been fully elucidated.

Purpose: To explore the protective activities of NXK in ischemia/reperfusion (IR)-induced HF through modulating the ratio of proinflammatory (M1) and anti-inflammatory (M2) macrophage populations and leading to the alleviation of inflammation.

Materials And Methods: In vivo, mice were subjected to myocardial IR to generate HF mouse models. Mice in the NXK group were treated with NXK for 28 days. Cardiac function was detected by echocardiography. Major lesions on mouse hearts were determined by hematoxylin-eosin (HE) staining, Masson staining, and TUNEL staining. Inflammatory cytokines were determined by enzyme-linked immunosorbent assay (ELISA) and qPCR examination. Flow cytometric analyses and qPCR examination were utilized for monitoring the temporal dynamics of macrophage infiltration following IR. In vitro, two polarized models were established by stimulating RAW264.7 cells with 200 ng/ml lipopolysaccharide (LPS) or 20 ng/ml interleukin-4 (IL-4). The RAW264.7 cells with nuclear factor-κB (NF-κB) overexpression was generated by transient transfection of NF-κB plasmids, and NXK intervention was conducted on this cell model to further clarify the involvement of NF-κB signaling in the NXK-mediated HF process.

Results: In the present study, NXK was found to significantly contribute the cardiac function and ameliorate cardiac fibrosis and apoptosis after myocardial IR injury in vivo, which may be partially due to a decrease in inflammation. We therefore hypothesized that NXK reduced inflammatory damage by modulating subtypes of macrophages. And the results demonstrated that the percentage of proinflammatory macrophages infiltrated in the post-IR period was reduced with NXK treatment, and thereby blunting the wave of proinflammatory response and shifting the peak of the anti-inflammatory macrophage-mediated wound healing process towards an earlier time point. The further investigation showed that macrophage polarization was mediated by NXK through inhibiting the phosphorylation and the nuclear translocation of NF-κB. Besides, the phosphorylated IKKβ and IκBα, upstream mediators of the NF-κB pathway, also decreased by NXK. Moreover, the overexpression of NF-κB partially reversed the NXK-induced favorable activities; and successfully compensated the suppressive effect on inflammation and the phosphorylation of NF-κB.

Conclusion: In conclude, our results demonstrated that NXK induced the cardioprotective effects against IR injury through a regulatory axis of IKKβ/IκBα/NF-κB-mediated macrophage polarization. The information gained from this study provide a possible natural strategy for anti-inflammatory treatment of HF.
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http://dx.doi.org/10.1016/j.phymed.2022.154093DOI Listing
July 2022

Cholesterol suppresses GOLM1-dependent selective autophagy of RTKs in hepatocellular carcinoma.

Cell Rep 2022 04;39(3):110712

General Surgery Department of Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai 200040, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China. Electronic address:

Aberrant activation of receptor tyrosine kinases (RTKs) and the subsequent metabolic reprogramming play critical roles in cancer progression. Our previous study has shown that Golgi membrane protein 1 (GOLM1) promotes hepatocellular carcinoma (HCC) metastasis by enhancing the recycling of RTKs. However, how this RTK recycling process is regulated and coupled with RTK degradation remains poorly defined. Here, we demonstrate that cholesterol suppresses the autophagic degradation of RTKs in a GOLM1-dependent manner. Further mechanistic studies reveal that GOLM1 mediates the selective autophagy of RTKs by interacting with LC3 through an LC3-interacting region (LIR), which is regulated by a cholesterol-mTORC1 axis. Lowering cholesterol by statins improves the efficacy of multiple tyrosine kinase inhibitors (TKIs) in vivo. Our findings indicate that cholesterol serves as a signal to switch GOLM1-RTK degradation to GOLM1-RTK recycling and suggest that lowering cholesterol by statin may be a promising combination strategy to improve the TKI efficiency in HCC.
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http://dx.doi.org/10.1016/j.celrep.2022.110712DOI Listing
April 2022

Coronavirus Entry Inhibitors.

Adv Exp Med Biol 2022 ;1366:101-121

Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China.

Coronaviruses (CoVs) are enveloped RNA viruses that widely exist in the environment. Several CoVs possess a strong ability to infect humans, termed as human coronavirus (HCoVs). Among seven known HCoVs, SARS-CoV-2, SARS-CoV, and MERS-CoV belong to highly pathogenic HCoVs, which can cause severe clinical symptoms and even death. Especially, the current COVID-19 pandemic severely threatens human survival and health, which emphasizes the importance of developing effective CoV vaccines and anti-CoV agents to protect humans from HCoV infections. Coronavirus entry inhibitors can block various processes in viral entry, such as receptor binding, proteolytic activation of spike protein, or virus-cell membrane fusion. Coronavirus entry inhibitors, alone or in combination with other drugs, play important roles in the treatment of coronavirus diseases. Thus, we summarize and discuss the development of coronavirus entry inhibitors in this chapter.
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http://dx.doi.org/10.1007/978-981-16-8702-0_7DOI Listing
April 2022

Preventive Effects of Anthocyanins from Murray in High-Fat Diet-Induced Obese Mice Are Related to the Regulation of Intestinal Microbiota and Inhibition of Pancreatic Lipase Activity.

Molecules 2022 Mar 26;27(7). Epub 2022 Mar 26.

Key Laboratory of Environmental Factors and Chronic Disease Control, School of Public Health and Management, Ningxia Medical University, Yinchuan 750004, China.

Murray (. ) has been used both as traditional Chinese medicine and food. Recent studies indicated that anthocyanins are the most abundant bioactive compounds in the . fruits. The purpose of this study was to investigate the preventive effects and the mechanism of the anthocycanins from the fruit of . (ACN) in high-fat diet-induced obese mice. In total, 24 male C57BL/6J mice were divided into three groups: control group (fed a normal diet), high-fat diet group (fed a high-fat diet, HFD), and HFD +ACN group (fed a high-fat diet and drinking distilled water that contained 0.8% crude extract of ACN). The results showed that ACN could significantly reduce the body weight, inhibit lipid accumulation in liver and white adipose tissue, and lower the serum total cholesterol and low-density lipoprotein cholesterol levels compared to that of mice fed a high-fat diet. 16S rRNA gene sequencing of bacterial DNA demonstrated that ACN prevent obesity by enhancing the diversity of cecal bacterial communities, lowering the -to- ratio, increasing the genera , and decreasing the genera . We also studied the inhibitory effect of ACN on pancreatic lipase. The results showed that ACN has a high affinity for pancreatic lipase and inhibits the activity of pancreatic lipase, with IC50 values of 1.80 (main compound anthocyanin) and 3.03 mg/mL (crude extract), in a competitive way. Furthermore, fluorescence spectroscopy studies showed that ACN can quench the intrinsic fluorescence of pancreatic lipase via a static mechanism. Taken together, these findings suggest that the anthocyanins from fruits could have preventive effects in high-fat-diet induced obese mice by regulating the intestinal microbiota and inhibiting the pancreatic lipase activity.
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http://dx.doi.org/10.3390/molecules27072141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9000451PMC
March 2022

Overexpression of HLH4 Inhibits Cell Elongation and Anthocyanin Biosynthesis in .

Cells 2022 03 24;11(7). Epub 2022 Mar 24.

Zhongzhi International Institute of Agricultural Biosciences, Shunde Graduate School, Research Center of Biology and Agriculture, University of Science and Technology Beijing (USTB), Beijing 100024, China.

In plants, many basic helix-loop-helix (bHLH) transcription factors are involved in controlling cell elongation. Three bHLH proteins, PACLOBTRAZOL RESISTANCE1 (PRE1), Cryptochrome Interacting Basic Helix-loop-helix 5 (CIB5), and Arabidopsis ILI1 binding bHLH1 (IBH1) form a triantagonistic system that antagonistically regulates cell elongation in a competitive manner. In this study, we identified a new player, HLH4, related to IBH1, that negatively regulates cell elongation in . Overexpression of HLH4 causes dwarf and dark green phenotypes and results in the downregulation of many key regulatory and enzymatic genes that participate in the anthocyanin biosynthetic pathway. HLH4 interacts with CIB5 and PRE1. By interacting with CIB5, HLH4 interferes with the activity of CIB5, and thus inhibiting the transcription of cell elongation-related genes regulated by CIB5, including and ( and ) and 7 and 17 ( and ). The interference of HLH4 on CIB5 is counteracted by PRE1, in which these bHLH proteins form a new tri-antagonistic system.
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http://dx.doi.org/10.3390/cells11071087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8997993PMC
March 2022

Light-absorption and fluorescence fingerprinting characteristics of water and methanol soluble organic compounds in PM in cold regions of Northeast China.

Sci Total Environ 2022 Apr 8:155081. Epub 2022 Apr 8.

Heilongjiang Metrology Institute of Measurement & Verification, Harbin 150036, China.

High-performance liquid chromatography-size exclusion chromatography and excitation-emission matrix (EEM) fluorescence spectroscopy were used to analyze the seasonal variations and potential sources of molecular weight (MW) separated light-absorbing chromophores and fluorophores of water-soluble organic compounds (WSOC) and methanol-soluble organic compounds (MSOC) in PM in cold areas of northern China. The results showed that the light-absorbing organics in MSOC had larger weight-average MW (M) (3.19 kDa) and number-average MW (M) (1.13 kDa) compared with WSOC (M: 1.41 kDa, M: 0.692 kDa). The light-absorption of organics showed a trend of winter>spring>autumn>summer and increased on air pollution days. Three fluorescent components including humic-like, protein-like, and terrestrial humic-like components in WSOC were extracted by parallel factor analysis (PARAFAC). Fluorophores in WSOC were dominated by humic-like and terrestrial humic-like components (67.7%). Three fluorescent components extracted from MSOC were low oxidation humic-like, polycyclic aromatic hydrocarbon (PAH)-like, and protein-like components respectively. It is worth noting that compared with WSOC, MSOC may have a higher human health risk due to the presence of PAH-like components. The combination of PARAFAC and self-organizing map had the potential to identify potential sources of fluorophores. It provided a new perspective for comprehensively exploring the characteristics of fluorophores in aerosols. This study provided a reference for further understanding the chemical composition and optical properties of organic aerosols in the cold regions of northern China.
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http://dx.doi.org/10.1016/j.scitotenv.2022.155081DOI Listing
April 2022

Boosting of serum neutralizing activity against the Omicron variant among recovered COVID-19 patients by BNT162b2 and CoronaVac vaccines.

EBioMedicine 2022 May 8;79:103986. Epub 2022 Apr 8.

State Key Laboratory for Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China; Department of Microbiology, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, China; Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong Special Administrative Region, China.; Department of Clinical Microbiology and Infection Control, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China. Electronic address:

Background: SARS-CoV-2 Omicron variant evades immunity from past infection or vaccination and is associated with a greater risk of reinfection among recovered COVID-19 patients. We assessed the serum neutralizing antibody (NAb) activity against Omicron variant (Omicron NAb) among recovered COVID-19 patients with or without vaccination.

Methods: In this prospective cohort study with 135 recovered COVID-19 patients, we determined the serum NAb titers against ancestral virus or variants using a live virus NAb assay. We used the receiver operating characteristic analysis to determine the optimal cutoff for a commercially-available surrogate NAb assay.

Findings: Among recovered COVID-19 patients, the serum live virus geometric mean Omicron NAb titer was statistically significantly higher among BNT162b2 recipients compared to non-vaccinated individuals (85.4 vs 5.6,P < 0.0001). The Omicron seropositive rates in live virus NAb test (NAb titer ≥10) were statistically significantly higher among BNT162b2 (90.6% [29/32];P < 0.0001) or CoronaVac (36.7% [11/30]; P = 0.0115) recipients when compared with non-vaccinated individuals (12.3% [9/73]). Subgroup analysis of CoronaVac recipients showed that the Omicron seropositive rates were higher among individuals with two doses than those with one dose (85.7% vs 21.7%; P = 0.0045). For the surrogate NAb assay, a cutoff of 109.1 AU/ml, which is 7.3-fold higher than the manufacturer's recommended cutoff, could achieve a sensitivity and specificity of 89.5% and 89.8%, respectively, in detecting Omicron NAb.

Interpretation: Among individuals with prior COVID-19, one dose of BNT162b2 or two doses of CoronaVac could induce detectable serum Omicron NAb. Our result would be particularly important for guiding vaccine policies in countries with COVID-19 vaccine shortage.

Funding: Health and Medical Research Fund, Richard and Carol Yu, Michael Tong (see acknowledgments for full list).
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http://dx.doi.org/10.1016/j.ebiom.2022.103986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8989491PMC
May 2022

Design of artificial α-helical peptides targeting both gp41 deep pocket and subpocket as potent HIV-1 fusion inhibitors.

Eur J Med Chem 2022 Jun 1;236:114336. Epub 2022 Apr 1.

Key Laboratory of Medical Molecular Virology of (MOE/NHC/CAMS), School of Basic Medical Sciences & Shanghai Public Health Clinical Center, Fudan University, 131 Dong An Road, Shanghai, 200032, China. Electronic address:

Both the deep pocket region and its neighboring subpocket site on the N-trimer of HIV-1 gp41 protein can serve as targets for the development of HIV-1 entry inhibitors. Pocket-binding domain (PBD)-containing peptides with the potential to inhibit HIV-1 fusion through targeting the deep pocket have been extensively exploited. However, using an artificial peptide strategy, we herein report the design of α-helical lipopeptides with non-native protein sequences as HIV-1 fusion inhibitors that can occupy both gp41 deep cavity and subpocket sites. The most active compound, PP24C, inhibited HIV-1 replication, including T20-resistant HIV-1 mutants, at low nanomolar level. Biophysical approaches revealed that both the artificial α-helical peptide P35A4 and its cholesterol-tagged peptide PP24C could bind to T21 peptide used as a target surrogate comprising both pockets. Our study offers a new template for the design of artificial anti-HIV-1 therapeutics and highlights the novel concept of peptide secondary structure-based virus fusion inhibitors.
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http://dx.doi.org/10.1016/j.ejmech.2022.114336DOI Listing
June 2022

Genetic diversity and evolution of goose astrovirus in the east of China.

Transbound Emerg Dis 2022 Apr 5. Epub 2022 Apr 5.

Shandong Key Laboratory of Disease Control and Breeding, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Science, Jinan, Shandong, China.

Goose astrovirus (GAstV), an agent of fatal visceral gout in goslings, has been widely circulating in eastern China since 2017, but little is known about its genetic diversity and systematic evolution. In this study, we isolated and sequenced nine nearly full-length GAstV genomes and conducted comprehensive genetic diversity and evolutionary analysis and compared them with other reported GAstV sequences. Our results indicated that two genotypic species of GAstV were circulating in China, and GAstV-2 subgenotype II-c had arisen as the dominant genotype in Shandong province and across the whole country. Multiple alignments of GAstV amino acid sequences revealed several characteristic mutations in GAstV-2 II-c strains, as well as additional residues in the nine new isolates which varied over time. Phylogenetic analysis of three open reading frames demonstrated different evolutionary histories. Evidence of natural recombination was also detected in GAstV, with most of the recombination occurring in the GAstV-2 II-c subgenotype. Molecular adaptation analyses revealed that the evolution of GAstV was shaped by strong negative selection, although a number of amino acids, which potentially affect host infection and cell entry, were subjected to positive pressure. Overall, these findings improve our understanding of the epidemiology and evolution of GAstV and may help in the development of vaccines and diagnostics.
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http://dx.doi.org/10.1111/tbed.14542DOI Listing
April 2022
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