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Mesenchyme homeobox 1 mediated-promotion of osteoblastic differentiation is negatively regulated by mir-3064-5p.

Differentiation 2021 Jun 10;120:19-27. Epub 2021 Jun 10.

Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Qingdao University, No. 59 Haier Road, Qingdao, 266000, Shandong, China. Electronic address:

Human mesenchymal stem cells (hMSCs) are multipotent cells that can be differentiated into different cell types including osteoblasts. Herein we aimed to assess the regulation of transcription factor mesenchyme homeobox 1 (Meox1) in the osteogenic differentiation of hMSCs and to determine the microRNA which targets on Meox1. Total RNA was extracted from the isolated ligamentum flavum tissue samples and cultured hMSCs, and the expression of Meox1 was assessed by RT-PCR and Western blot assays. Read More

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Structural basis for the coiled-coil architecture of human CtIP.

Open Biol 2021 Jun 16;11(6):210060. Epub 2021 Jun 16.

Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK.

The DNA repair factor CtIP has a critical function in double-strand break (DSB) repair by homologous recombination, promoting the assembly of the repair apparatus at DNA ends and participating in DNA-end resection. However, the molecular mechanisms of CtIP function in DSB repair remain unclear. Here, we present an atomic model for the three-dimensional architecture of human CtIP, derived from a multi-disciplinary approach that includes X-ray crystallography, small-angle X-ray scattering (SAXS) and diffracted X-ray tracking (DXT). Read More

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Self-Assembled Nanobodies as Selectively Targeted, Nanostructured, and Multivalent Materials.

ACS Appl Mater Interfaces 2021 Jun 15. Epub 2021 Jun 15.

Laboratory for Environmental and Life Sciences, University of Nova Gorica Nova Gorica 5000, Slovenia.

Nanobodies represent valuable tools in advanced therapeutic strategies but their small size (∼2.5 × ∼ 4 nm) and limited valence for interactions might pose restrictions for applications, especially regarding their modest capacity for multivalent and cooperative interaction. In this work, modular protein constructs have been designed, in which nanobodies are fused to protein domains to provide further functionalities and to favor oligomerization into stable self-assembled nanoparticles. Read More

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Impacts of OrX and cAMP-insensitive Orco to the insect olfactory heteromer activity.

Mol Biol Rep 2021 Jun 11. Epub 2021 Jun 11.

Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.

Insect odorant receptors (ORs) have been suggested to function as ligand-gated cation channels, with OrX/Orco heteromers combining ionotropic and metabotropic activity. The latter is mediated by different G proteins and results in Orco self-activation by cyclic nucleotide binding. In this contribution, we co-express the odor-specific subunits DmOr49b and DmOr59b with either wild-type Orco or an Orco-PKC mutant lacking cAMP activation heterologously in mammalian cells. Read More

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Subcellular dynamics of estrogen-related receptors involved in transrepression through interactions with scaffold attachment factor B1.

Histochem Cell Biol 2021 Jun 15. Epub 2021 Jun 15.

Department of Anatomy and Neurobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan.

Estrogen-related receptor (ERR), a member of the nuclear receptor superfamily, consists of three subtypes (α, β, γ) and has strong homology with estrogen receptor. No endogenous ligands have been identified for ERRs, but they play key roles in metabolic, hormonal, and developmental processes as transcription factors without ligand binding. Although subnuclear dynamics are essential for nuclear events including nuclear receptor-mediated transcriptional regulation, the dynamics of ERRs are poorly understood. Read More

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Gene Conversion Facilitates the Adaptive Evolution of Self-Resistance in Highly Toxic Newts.

Mol Biol Evol 2021 Jun 15. Epub 2021 Jun 15.

Department of Biological Sciences, Virginia Tech, Blacksburg, United States.

Reconstructing the histories of complex adaptations and identifying the evolutionary mechanisms underlying their origins are two of the primary goals of evolutionary biology. Taricha newts, which contain high concentrations of the deadly toxin tetrodotoxin (TTX) as an antipredator defense, have evolved resistance to self-intoxication, which is a complex adaptation requiring changes in six paralogs of the voltage-gated sodium channel (Nav) gene family, the physiological target of TTX. Here, we reconstruct the origins of TTX self-resistance by sequencing the entire Nav gene family in newts and related salamanders. Read More

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The CaM1-Associated CCaMK-MKK1/6 cascade positively affects the lateral root growth through auxin signaling under salt stress in rice.

J Exp Bot 2021 Jun 15. Epub 2021 Jun 15.

MOA Key Laboratory of Crop Ecophysiology and Farming System in the Middle Reaches of the Yangtze River, Huazhong Agricultural University, Wuhan, China.

CCaMKs and MAPKKs are two kinases that regulate salt stress response in plants. It remains unclear, however, how they cooperatively affect the lateral root growth under salt stress. Here, two conserved phosphorylation sites (S102 and T118) of OsCaM1 were identified, and affected the capability of binding to Ca 2+  in vitro and kinase activity of OsCCaMK in vivo. Read More

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Cryo-EM structures of Lassa and Machupo virus polymerases complexed with cognate regulatory Z proteins identify targets for antivirals.

Nat Microbiol 2021 Jun 14. Epub 2021 Jun 14.

Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China.

Zoonotic arenaviruses can lead to life-threating diseases in humans. These viruses encode a large (L) polymerase that transcribes and replicates the viral genome. At the late stage of replication, the multifunctional Z protein interacts with the L polymerase to shut down RNA synthesis and initiate virion assembly. Read More

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Pseudogene ACTBP2 increases blood-brain barrier permeability by promoting KHDRBS2 transcription through recruitment of KMT2D/WDR5 in Aβ microenvironment.

Cell Death Discov 2021 Jun 14;7(1):142. Epub 2021 Jun 14.

Department of Neurobiology, School of life Sciences, China Medical University, Shenyang, China.

The blood-brain barrier (BBB) has a vital role in maintaining the homeostasis of the central nervous system (CNS). Changes in the structure and function of BBB can accelerate Alzheimer's disease (AD) development. β-Amyloid (Aβ) deposition is the major pathological event of AD. Read More

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CircASXL1 knockdown represses the progression of colorectal cancer by downregulating GRIK3 expression by sponging miR-1205.

World J Surg Oncol 2021 Jun 14;19(1):176. Epub 2021 Jun 14.

Department of General Surgery, Shanghai Fengxian Central Hospital, No. 6600, Nanfeng Road, Nanqiao New Town, Fengxian District, Shanghai, 201400, China.

Background: Colorectal cancer (CRC) is a common aggressive tumor that poses a heavy burden to human health. An increasing number of studies have reported that circular RNA (circRNA) is involved in the progression of CRC. In this study, the special profiles of circASXL1 (circ_0001136) in CRC progression were revealed. Read More

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Structural properties of ultra-small thorium and uranium dioxide nanoparticles embedded in a covalent organic framework.

Chem Sci 2020 Apr 28;11(18):4648-4668. Epub 2020 Apr 28.

Lawrence Berkeley National Laboratory Berkeley CA 94720 USA

We report the structural properties of ultra-small ThO and UO nanoparticles (NPs), which were synthesized without strong binding surface ligands by employing a covalent organic framework (COF-5) as an inert template. The resultant NPs were used to observe how structural properties are affected by decreasing grain size within bulk actinide oxides, which has implications for understanding the behavior of nuclear fuel materials. Through a comprehensive characterization strategy, we gain insight regarding how structure at the NP surface differs from the interior. Read More

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Recruitment of receptors at supported lipid bilayers promoted by the multivalent binding of ligand-modified unilamellar vesicles.

Chem Sci 2020 Mar 9;11(12):3307-3315. Epub 2020 Mar 9.

Molecular Nanofabrication Group, MESA+ Institute for Nanotechnology, Faculty of Science and Technology, University of Twente P.O. Box 217 Enschede 7500 AE The Netherlands

The development of model systems that mimic biological interactions and allow the control of both receptor and ligand densities, is essential for a better understanding of biomolecular processes, such as the recruitment of receptors at interfaces, at the molecular level. Here we report a model system based on supported lipid bilayers (SLBs) for the investigation of the clustering of receptors at their interface. Biotinylated SLBs, used as cell membrane mimics, were functionalized with streptavidin (SAv), used here as receptor. Read More

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The lncRNA PAHRF functions as a competing endogenous RNA to regulate MST1 expression by sponging miR-23a-3p in pulmonary arterial hypertension.

Vascul Pharmacol 2021 Jun 11:106886. Epub 2021 Jun 11.

Department of Pharmacy, The First People's Hospital of Lianyungang, Lianyungang 222061, China; Department of Pharmacy, The Affiliated Lianyungang Hospital of Xuzhou Medical University/The First People's Hospital of Lianyungang, Lianyungang 222061, China.

Background: Emerging evidence has shown that long non-coding RNA (lncRNA) plays important roles in the development of pulmonary arterial hypertension (PAH). However, some new lncRNAs in patients with PAH are still lacking research. Herein, we examined the expression and role of lncRNA (pulmonary arterial hypertension related factor, PAHRF) in PAH. Read More

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Achieving Efficient Fragment Screening at XChem Facility at Diamond Light Source.

J Vis Exp 2021 05 29(171). Epub 2021 May 29.

Diamond Light Source Ltd, Harwell Science and Innovation Campus; Research Complex at Harwell, Harwell Science and Innovation Campus; Structural Genomics Consortium, University of Oxford; Centre for Medicines Discovery, University of Oxford; Department of Biochemistry, University of Johannesburg;

In fragment-based drug discovery, hundreds or often thousands of compounds smaller than ~300 Da are tested against the protein of interest to identify chemical entities that can be developed into potent drug candidates. Since the compounds are small, interactions are weak, and the screening method must therefore be highly sensitive; moreover, structural information tends to be crucial for elaborating these hits into lead-like compounds. Therefore, protein crystallography has always been a gold-standard technique, yet historically too challenging to find widespread use as a primary screen. Read More

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Skin Pharmacokinetics of Transdermal Scopolamine: Measurements and Modeling.

Mol Pharm 2021 Jun 14. Epub 2021 Jun 14.

Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, U.K.

Prediction of skin absorption and local bioavailability from topical formulations remains a difficult task. An important challenge in forecasting topical bioavailability is the limited information available about local and systemic drug concentrations post application of topical drug products. Commercially available transdermal patches, such as Scopoderm (Novartis Consumer Health UK), offer an opportunity to test these experimental approaches as systemic pharmacokinetic data are available with which to validate a predictive model. Read More

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Dynamic Profiling of β-Coronavirus 3CL M Protease Ligand-Binding Sites.

J Chem Inf Model 2021 Jun 14. Epub 2021 Jun 14.

UCL School of Pharmacy, London WC1N 1AX, U.K.

β-coronavirus (CoVs) alone has been responsible for three major global outbreaks in the 21st century. The current crisis has led to an urgent requirement to develop therapeutics. Even though a number of vaccines are available, alternative strategies targeting essential viral components are required as a backup against the emergence of lethal viral variants. Read More

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ORP2 couples LDL-cholesterol transport to FAK activation by endosomal cholesterol/PI(4,5)P exchange.

EMBO J 2021 Jun 14:e106871. Epub 2021 Jun 14.

Department of Anatomy and Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

Low-density lipoprotein (LDL)-cholesterol delivery from late endosomes to the plasma membrane regulates focal adhesion dynamics and cell migration, but the mechanisms controlling it are poorly characterized. Here, we employed auxin-inducible rapid degradation of oxysterol-binding protein-related protein 2 (ORP2/OSBPL2) to show that endogenous ORP2 mediates the transfer of LDL-derived cholesterol from late endosomes to focal adhesion kinase (FAK)-/integrin-positive recycling endosomes in human cells. In vitro, cholesterol enhances membrane association of FAK to PI(4,5)P -containing lipid bilayers. Read More

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Combination of UPLC-Q-TOF/MS and Network Pharmacology to Reveal the Mechanism of Qizhen Decoction in the Treatment of Colon Cancer.

ACS Omega 2021 Jun 26;6(22):14341-14360. Epub 2021 May 26.

College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.

Traditional Chinese medicine (TCM) has been utilized for the treatment of colon cancer. Qizhen decoction (QZD), a potential compound prescription of TCM, possesses multiple biological activities. It has been proven clinically effective in the treatment of colon cancer. Read More

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Investigation of the Mechanism of Complement System in Diabetic Nephropathy via Bioinformatics Analysis.

J Diabetes Res 2021 24;2021:5546199. Epub 2021 May 24.

Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072 Sichuan, China.

Objectives: Diabetic nephropathy (DN) is a major cause of end-stage renal disease (ESRD) throughout the world, and the identification of novel biomarkers via bioinformatics analysis could provide research foundation for future experimental verification and large-group cohort in DN models and patients.

Methods: GSE30528, GSE47183, and GSE104948 were downloaded from Gene Expression Omnibus (GEO) database to find differentially expressed genes (DEGs). The difference of gene expression between normal renal tissues and DN renal tissues was firstly screened by GEO2R. Read More

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Altered Glycosylation in the Aging Heart.

Front Mol Biosci 2021 28;8:673044. Epub 2021 May 28.

Institute of Human Genetics, University Hospital Jena, Friedrich Schiller University, Jena, Germany.

Cardiovascular disease is one of the leading causes of death in developed countries. Because the incidence increases exponentially in the aging population, aging is a major risk factor for cardiovascular disease. Cardiac hypertrophy, fibrosis and inflammation are typical hallmarks of the aged heart. Read More

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Unveiling the molecular mechanism of SARS-CoV-2 main protease inhibition from 137 crystal structures using algebraic topology and deep learning.

Chem Sci 2020 Sep 30;11(44):12036-12046. Epub 2020 Sep 30.

Department of Mathematics, Michigan State University MI 48824 USA

Currently, there is neither effective antiviral drugs nor vaccine for coronavirus disease 2019 (COVID-19) caused by acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Due to its high conservativeness and low similarity with human genes, SARS-CoV-2 main protease (M) is one of the most favorable drug targets. However, the current understanding of the molecular mechanism of M inhibition is limited by the lack of reliable binding affinity ranking and prediction of existing structures of M-inhibitor complexes. Read More

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September 2020

Modified cyclodextrins solubilize elemental sulfur in water and enable biological sulfane sulfur delivery.

Chem Sci 2020 Oct 5;11(43):11777-11784. Epub 2020 Oct 5.

Department of Chemistry and Biochemistry, Materials Science Institute, Knight Campus for Accelerating Scientific Impact, Institute of Molecular Biology, University of Oregon Eugene OR 97403 USA

An important form of biological sulfur is sulfane sulfur, or S, which is found in polysulfide and persulfide compounds as well as in elemental sulfur. Sulfane sulfur, often in the form of S, functions as a key energy source in the metabolic processes of thermophilic Archaean organisms found in sulfur-rich environments and can be metabolized both aerobically and anaerobically by different archaeons. Despite this importance, S has a low solubility in water (∼19 nM), raising questions of how it can be made chemically accessible in complex environments. Read More

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October 2020

Carbohydrate-binding module -mannosylation alters binding selectivity to cellulose and lignin.

Chem Sci 2020 Aug 19;11(34):9262-9271. Epub 2020 Aug 19.

Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College Beijing 100050 China

Improved understanding of the effect of protein glycosylation is expected to provide the foundation for the design of protein glycoengineering strategies. In this study, we examine the impact of -glycosylation on the binding selectivity of a model Family 1 carbohydrate-binding module (CBM), which has been shown to be one of the primary sub-domains responsible for non-productive lignin binding in multi-modular cellulases. Specifically, we examine the relationship between glycan structure and the binding specificity of the CBM to cellulose and lignin substrates. Read More

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Templating S100A9 amyloids on Aβ fibrillar surfaces revealed by charge detection mass spectrometry, microscopy, kinetic and microfluidic analyses.

Chem Sci 2020 Jun 17;11(27):7031-7039. Epub 2020 Jun 17.

Department of Medical Biochemistry and Biophysics, Umeå University SE-90187 Umeå Sweden

The mechanism of amyloid co-aggregation and its nucleation process are not fully understood in spite of extensive studies. Deciphering the interactions between proinflammatory S100A9 protein and Aβ peptide in Alzheimer's disease is fundamental since inflammation plays a central role in the disease onset. Here we use innovative charge detection mass spectrometry (CDMS) together with biophysical techniques to provide mechanistic insight into the co-aggregation process and differentiate amyloid complexes at a single particle level. Read More

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Structural trends in the dehydrogenation selectivity of palladium alloys.

Chem Sci 2020 May 5;11(19):5066-5081. Epub 2020 May 5.

Davidson School of Chemical Engineering, Purdue University West Lafayette IN 47907 USA

Alloying is well-known to improve the dehydrogenation selectivity of pure metals, but there remains considerable debate about the structural and electronic features of alloy surfaces that give rise to this behavior. To provide molecular-level insights into these effects, a series of Pd intermetallic alloy catalysts with Zn, Ga, In, Fe and Mn promoter elements was synthesized, and the structures were determined using X-ray absorption spectroscopy (XAS) and synchrotron X-ray diffraction (XRD). The alloys all showed propane dehydrogenation turnover rates 5-8 times higher than monometallic Pd and selectivity to propylene of over 90%. Read More

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FOXO3a Protects against Kidney Injury in Type II Diabetic Nephropathy by Promoting Sirt6 Expression and Inhibiting Smad3 Acetylation.

Oxid Med Cell Longev 2021 26;2021:5565761. Epub 2021 May 26.

Department of Nephrology, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, 1158 Gongyuan East Road, Qingpu District, Shanghai 201700, China.

Diabetic nephropathy (DN) is the most common cause of end-stage renal disease. Although numerous reports have demonstrated a correlation between epithelial-mesenchymal transition (EMT) and renal fibrosis, how these processes lead to tubular dysfunction remains unclear. Here, we show that FOXO3a protects kidneys from injury in type II DN by increasing Sirt6 expression, which deacetylates Smad3 and inhibits its transcriptional activity. Read More

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Genome-Wide Analysis of Coding and Non-coding RNA Reveals a Conserved miR164-NAC-mRNA Regulatory Pathway for Disease Defense in .

Front Genet 2021 28;12:668940. Epub 2021 May 28.

Beijing Advanced Innovation Center for Tree Breeding by Molecular Design, College of Biological Sciences and Technology, Beijing Forestry University, Beijing, China.

MicroRNAs (miRNAs) contribute to plant defense responses by increasing the overall genetic diversity; however, their origins and functional importance in plant defense remain unclear. Here, we employed Illumina sequencing technology to assess how miRNA and messenger RNA (mRNA) populations vary in the Chinese white poplar () during a leaf black spot fungus () infection. We sampled RNAs from infective leaves at conidia germinated stage [12 h post-inoculation (hpi)], infective vesicles stage (24 hpi), and intercellular infective hyphae stage (48 hpi), three essential stages associated with plant colonization and biotrophic growth in fungi. Read More

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A VH-Fc Fusion Targeted to the Chloroplast Thylakoid Lumen Assembles and Neutralizes Enterohemorrhagic O157:H7.

Front Plant Sci 2021 28;12:686421. Epub 2021 May 28.

Agriculture and Agri-Food Canada, London Research and Development Centre, London, ON, Canada.

Chimeric fusion proteins comprising a single domain antibody (VH) fused to a crystallizable fragment (Fc) of an immunoglobulin are modular glycoproteins that are becoming increasingly in demand because of their value as diagnostics, research reagents and passive immunization therapeutics. Because ER-associated degradation and misfolding may potentially be limiting factors in the oxidative folding of VH-Fc fusion proteins in the ER, we sought to explore oxidative folding in an alternative sub-compartment, the chloroplast thylakoid lumen, and determine its viability in a molecular farming context. We developed a set of in-house expression vectors for transient transformation of leaves that target a VH-Fc to the thylakoid lumen via either secretory (Sec) or twin-arginine translocation (Tat) import pathways. Read More

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Exogenous Gene Expression and Insect Resistance in Dual Bt Toxin × 'Neva' Transgenic Plants.

Front Plant Sci 2021 28;12:660226. Epub 2021 May 28.

Forest Department, Forestry College, Hebei Agricultural University, Baoding, China.

(Bt) insecticidal protein genes are important tools in efforts to develop insect resistance in poplar. In this study, the and Bt toxin genes were simultaneously transformed into the poplar variety × 'Neva' by -mediated transformation to explore the exogenous gene expression and insect resistance, and to examine the effects of Bt toxin on the growth and development of larvae after feeding on the transgenic plant. Integration and expression of the transgenes were determined by molecular analyses and the insect resistance of transgenic lines was evaluated in feeding experiments. Read More

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PSDX: A Comprehensive Multi-Omics Association Database of With a Focus on the Secondary Growth in Response to Stresses.

Front Plant Sci 2021 20;12:655565. Epub 2021 May 20.

Basic Forestry and Proteomics Research Center, College of Forestry, Fujian Agriculture and Forestry University, Fuzhou, China.

() is a model tree for the investigation of wood formation. In recent years, researchers have generated a large number of high-throughput sequencing data in . However, no comprehensive database that provides multi-omics associations for the investigation of secondary growth in response to diverse stresses has been reported. Read More

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