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  1. Article ; Online: Measuring cigarette smoking-induced cortical dopamine release: A [¹¹C]FLB-457 PET study.

    Wing, Victoria C / Payer, Doris E / Houle, Sylvain / George, Tony P / Boileau, Isabelle

    Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

    2015  Volume 40, Issue 6, Page(s) 1417–1427

    Abstract: ... radiotracers permit the measurement of cortical DA in humans using positron emission tomography (PET). [(11)C ... relapse, these associations warrant investigation in a larger sample. [(11)C]FLB-457 PET imaging ... reinstatement of smoking. Voxel-wise [(11)C]-FLB-457-binding potential (BPND) in the frontal lobe, insula, and ...

    Abstract Striatal dopamine (DA) is thought to have a fundamental role in the reinforcing effects of tobacco smoking and nicotine. Microdialysis studies indicate that nicotine also increases DA in extrastriatal brain areas, but much less is known about its role in addiction. High-affinity D2/3 receptor radiotracers permit the measurement of cortical DA in humans using positron emission tomography (PET). [(11)C]FLB-457 PET scans were conducted in 10 nicotine-dependent daily smokers after overnight abstinence and reinstatement of smoking. Voxel-wise [(11)C]-FLB-457-binding potential (BPND) in the frontal lobe, insula, and limbic regions was estimated in the two conditions. Paired t-tests showed BPND values were reduced following smoking (an indirect index of DA release). The overall peak t was located in the cingulate gyrus, which was part of a larger medial cluster (BPND change -12.1±9.4%) and this survived false discovery rate correction for multiple comparisons. Clusters were also identified in the left anterior cingulate cortex/medial frontal gyrus, bilateral prefrontal cortex (PFC), bilateral amygdala, and the left insula. This is the first demonstration of tobacco smoking-induced cortical DA release in humans; it may be the result of both pharmacological (nicotine) and non-pharmacological factors (tobacco cues). Abstinence increased craving but had minimal cognitive effects, thus limiting correlation analyses. However, given that the cingulate cortex, PFC, insula, and amygdala are thought to have important roles in tobacco craving, cognition, and relapse, these associations warrant investigation in a larger sample. [(11)C]FLB-457 PET imaging may represent a useful tool to investigate individual differences in tobacco addiction severity and treatment response.
    MeSH term(s) Adult ; Brain Mapping ; Carbon Radioisotopes ; Cerebral Cortex/diagnostic imaging ; Cerebral Cortex/metabolism ; Craving/physiology ; Dopamine/metabolism ; Dopamine Antagonists ; Female ; Humans ; Male ; Positron-Emission Tomography ; Pyrrolidines ; Radiopharmaceuticals ; Salicylamides ; Smoking/metabolism ; Smoking/psychology ; Tobacco Use Disorder/diagnostic imaging ; Tobacco Use Disorder/metabolism ; Tobacco Use Disorder/psychology
    Chemical Substances Carbon Radioisotopes ; Dopamine Antagonists ; Pyrrolidines ; Radiopharmaceuticals ; Salicylamides ; FLB 457 (107188-66-9) ; Dopamine (VTD58H1Z2X)
    Language English
    Publishing date 2015-05
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 639471-1
    ISSN 1740-634X ; 0893-133X
    ISSN (online) 1740-634X
    ISSN 0893-133X
    DOI 10.1038/npp.2014.327
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: The N6-methyladenosine demethylase ALKBH5 regulates the hypoxic HBV transcriptome.

    Tsukuda, Senko / Harris, James M / Magri, Andrea / Balfe, Peter / Siddiqui, Aleem / Wing, Peter A C / McKeating, Jane A

    PLoS pathogens

    2024  Volume 20, Issue 1, Page(s) e1011917

    Abstract: Chronic hepatitis B is a global health problem and current treatments only suppress hepatitis B virus (HBV) infection, highlighting the need for new curative treatments. Oxygen levels influence HBV replication and we previously reported that hypoxia ... ...

    Abstract Chronic hepatitis B is a global health problem and current treatments only suppress hepatitis B virus (HBV) infection, highlighting the need for new curative treatments. Oxygen levels influence HBV replication and we previously reported that hypoxia inducible factors (HIFs) activate the basal core promoter (BCP). Here we show that the hypoxic-dependent increase in BCP-derived transcripts is dependent on N6-methyladenosine (m6A) modifications in the 5' stem loop that regulate RNA half-life. Application of a probe-enriched long-read sequencing method to accurately map the HBV transcriptome showed an increased abundance of pre-genomic RNA under hypoxic conditions. Mapping the transcription start sites of BCP-RNAs identified a role for hypoxia to regulate pre-genomic RNA splicing that is dependent on m6A modification. Bioinformatic analysis of published single cell RNA-seq of murine liver showed an increased expression of the RNA demethylase ALKBH5 in the peri-central low oxygen region. In vitro studies with a human hepatocyte derived HepG2-NTCP cell line showed increased ALKBH5 gene expression under hypoxic conditions and a concomitant reduction in m6A-modified HBV BCP-RNA and host RNAs. Silencing the demethylase reduced the level of BCP-RNAs and host gene (CA9, NDRG1, VEGFA, BNIP3, FUT11, GAP and P4HA1) transcripts and this was mediated via reduced HIFα expression. In summary, our study highlights a previously unrecognized role for ALKBH5 in orchestrating viral and cellular transcriptional responses to low oxygen.
    MeSH term(s) Animals ; Humans ; Mice ; AlkB Homolog 5, RNA Demethylase/genetics ; AlkB Homolog 5, RNA Demethylase/metabolism ; Fucosyltransferases/genetics ; Hepatitis B/genetics ; Hepatitis B virus/metabolism ; Hypoxia ; Oxygen ; RNA ; Transcriptome
    Chemical Substances AlkB Homolog 5, RNA Demethylase (EC 1.14.11.-) ; ALKBH5 protein, human (EC 1.14.11.-) ; Fucosyltransferases (EC 2.4.1.-) ; FUT11 protein, human (EC 2.4.1.-) ; Oxygen (S88TT14065) ; RNA (63231-63-0) ; ALKBH5 protein, mouse (EC 1.14.11.-)
    Language English
    Publishing date 2024-01-16
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2205412-1
    ISSN 1553-7374 ; 1553-7374
    ISSN (online) 1553-7374
    ISSN 1553-7374
    DOI 10.1371/journal.ppat.1011917
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Oxygen-dependent histone lysine demethylase 4 restricts hepatitis B virus replication.

    Harris, James M / Magri, Andrea / Faria, Ana Rita / Tsukuda, Senko / Balfe, Peter / Wing, Peter A C / McKeating, Jane A

    The Journal of biological chemistry

    2024  Volume 300, Issue 3, Page(s) 105724

    Abstract: Mammalian cells have evolved strategies to regulate gene expression when oxygen is limited. Hypoxia-inducible factors (HIF) are the major transcriptional regulators of host gene expression. We previously reported that HIFs bind and activate hepatitis B ... ...

    Abstract Mammalian cells have evolved strategies to regulate gene expression when oxygen is limited. Hypoxia-inducible factors (HIF) are the major transcriptional regulators of host gene expression. We previously reported that HIFs bind and activate hepatitis B virus (HBV) DNA transcription under low oxygen conditions; however, the global cellular response to low oxygen is mediated by a family of oxygenases that work in concert with HIFs. Recent studies have identified a role for chromatin modifiers in sensing cellular oxygen and orchestrating transcriptional responses, but their role in the HBV life cycle is as yet undefined. We demonstrated that histone lysine demethylase 4 (KDM4) can restrict HBV, and pharmacological or oxygen-mediated inhibition of the demethylase increases viral RNAs derived from both episomal and integrated copies of the viral genome. Sequencing studies demonstrated that KDM4 is a major regulator of the hepatic transcriptome, which defines hepatocellular permissivity to HBV infection. We propose a model where HBV exploits cellular oxygen sensors to replicate and persist in the liver. Understanding oxygen-dependent pathways that regulate HBV infection will facilitate the development of physiologically relevant cell-based models that support efficient HBV replication.
    MeSH term(s) Humans ; DNA, Viral/genetics ; Genome, Viral/genetics ; Hepatitis B/enzymology ; Hepatitis B/metabolism ; Hepatitis B/virology ; Hepatitis B virus/genetics ; Hepatitis B virus/growth & development ; Hepatitis B virus/metabolism ; Jumonji Domain-Containing Histone Demethylases/metabolism ; Liver/enzymology ; Liver/metabolism ; Liver/virology ; Oxygen/metabolism ; Plasmids/genetics ; Transcriptome ; Virus Replication/genetics
    Chemical Substances DNA, Viral ; Jumonji Domain-Containing Histone Demethylases (EC 1.14.11.-) ; Oxygen (S88TT14065)
    Language English
    Publishing date 2024-02-05
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1016/j.jbc.2024.105724
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Discovery of novel direct small-molecule inhibitors targeting HIF-2α using structure-based virtual screening, molecular dynamics simulation, and MM-GBSA calculations.

    Yazdani, Behnaz / Sirous, Hajar / Enguita, Francisco J / Brogi, Simone / Wing, Peter A C / Fassihi, Afshin

    Molecular diversity

    2023  

    Abstract: Hypoxia-inducible factors (HIFs) are the main regulatory factors implicated in the adaptation of cancer cells to hypoxic stress, which has provoked much interest as an attractive target for the design of promising chemotherapeutic agents. Since indirect ... ...

    Abstract Hypoxia-inducible factors (HIFs) are the main regulatory factors implicated in the adaptation of cancer cells to hypoxic stress, which has provoked much interest as an attractive target for the design of promising chemotherapeutic agents. Since indirect HIF inhibitors (HIFIs) lead to the occurrence of various side effects, the need of the hour is to develop direct HIFIs, physically interacting with important functional domains within the HIF protein structure. Accordingly, in the present study, it was attempted to develop an exhaustive structure-based virtual screening (VS) process coupled with molecular docking, molecular dynamic (MD) simulation, and MM-GBSA calculations for the identification of novel direct inhibitors against the HIF-2α subunit. For this purpose, a focused library of over 200,000 compounds from the NCI database was used for VS against the PAS-B domain of the target protein, HIF-2α. This domain was suggested to be a possible ligand-binding site, which is characterized by a large internal hydrophobic cavity, unique to the HIF-2α subunit. The top-ranked compounds, NSC106416, NSC217021, NSC217026, NSC215639, and NSC277811 with the best docking scores were taken up for the subsequent in silico ADME properties and PAINS filtration. The selected drug-like hits were employed for carrying out MD simulation which was followed by MM-GBSA calculations to retrieve the candidates showing the highest in silico binding affinity towards the PAS-B domain of HIF-2α. The analysis of results indicated that all molecules, except the NSC277811, fulfilled necessary drug-likeness properties. Four selected drug-like candidates, NSC106416, NSC217021, NSC217026, and NSC215639 were found to expose the stability profiles within the cavity located inside the PAS-B domain of HIF-2α over simulation time. Finally, the results of the MM-GBSA rescoring method were indicative of the highest binding affinity of NSC217026 for the binding site of the HIF-2α PAS-B domain among selected final hits. Consequently, the hit NSC217026 could serve as a promising scaffold for further optimization toward the design of direct HIF-2α inhibitors for cancer therapy.
    Language English
    Publishing date 2023-04-29
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 1376507-3
    ISSN 1573-501X ; 1381-1991
    ISSN (online) 1573-501X
    ISSN 1381-1991
    DOI 10.1007/s11030-023-10650-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: An enrichment protocol and analysis pipeline for long read sequencing of the hepatitis B virus transcriptome.

    Ng, Esther / Dobrica, Mihaela-Olivia / Harris, James M / Wu, Yanxia / Tsukuda, Senko / Wing, Peter A C / Piazza, Paolo / Balfe, Peter / Matthews, Philippa C / Ansari, M Azim / McKeating, Jane A

    The Journal of general virology

    2023  Volume 104, Issue 5

    Abstract: Hepatitis B virus (HBV) is one of the smallest human DNA viruses and its 3.2 Kb genome encodes multiple overlapping open reading frames, making its viral transcriptome challenging to dissect. Previous studies have combined quantitative PCR and Next ... ...

    Abstract Hepatitis B virus (HBV) is one of the smallest human DNA viruses and its 3.2 Kb genome encodes multiple overlapping open reading frames, making its viral transcriptome challenging to dissect. Previous studies have combined quantitative PCR and Next Generation Sequencing to identify viral transcripts and splice junctions, however the fragmentation and selective amplification used in short read sequencing precludes the resolution of full length RNAs. Our study coupled an oligonucleotide enrichment protocol with state-of-the-art long read sequencing (PacBio) to identify the repertoire of HBV RNAs. This methodology provides sequencing libraries where up to 25 % of reads are of viral origin and enable the identification of canonical (unspliced), non-canonical (spliced) and chimeric viral-human transcripts. Sequencing RNA isolated from
    MeSH term(s) Humans ; Transcriptome ; Hepatitis B virus/genetics ; High-Throughput Nucleotide Sequencing ; RNA, Viral/genetics
    Chemical Substances RNA, Viral
    Language English
    Publishing date 2023-05-17
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 219316-4
    ISSN 1465-2099 ; 0022-1317
    ISSN (online) 1465-2099
    ISSN 0022-1317
    DOI 10.1099/jgv.0.001856
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: The A150V Polymorphism of Genotype 3 Hepatitis C Virus Polymerase Inhibits Interferon Alfa by Suppressing Protein Kinase R Activation.

    Lee, Wing-Yiu Jason / Jones, Meleri / Wing, Peter A C / Rajagopal, Swathi / Foster, Graham R

    Cellular and molecular gastroenterology and hepatology

    2020  Volume 11, Issue 4, Page(s) 1163–1175

    Abstract: Background & aims: Despite recent advances in antiviral therapy for hepatitis C virus (HCV ...

    Abstract Background & aims: Despite recent advances in antiviral therapy for hepatitis C virus (HCV), a proportion of patients with genotype 3 (G3) HCV infection do not respond to current all oral treatment regimens. Genomic analyses have identified key polymorphisms correlating with increased resistance to direct-acting antivirals. We previously reported that amino the acid polymorphism, A150V, in the polymerase (NS5B) of G3 HCV reduces response to sofosbuvir. We now demonstrate that this polymorphism alters the response to interferon alpha.
    Methods: Quantitative polymerase chain reaction, immunofluorescence, luciferase activity assay, immunoblotting, and flow cytometry were used to study the antiviral effect of interferon (IFN) on DBN G3 HCV-infected cells and G3 HCV replicons.
    Results: We show the presence of the A150V polymorphism markedly reduces the response to IFN alpha (IC
    Conclusions: These results demonstrate that polymorphisms reducing response rates to direct-acting antivirals may function beyond conferring drug resistance by modulating the intrinsic cellular antiviral response.
    MeSH term(s) Antiviral Agents/pharmacology ; Carcinoma, Hepatocellular/genetics ; Carcinoma, Hepatocellular/pathology ; Carcinoma, Hepatocellular/virology ; Hepacivirus/drug effects ; Hepacivirus/genetics ; Hepatitis C/complications ; Hepatitis C/drug therapy ; Hepatitis C/genetics ; Hepatitis C/pathology ; Humans ; Interferon-alpha/pharmacology ; Liver Neoplasms/genetics ; Liver Neoplasms/pathology ; Liver Neoplasms/virology ; Polymorphism, Genetic ; RNA, Viral/genetics ; RNA-Dependent RNA Polymerase/genetics ; Replicon/genetics ; Tumor Cells, Cultured ; Viral Nonstructural Proteins/genetics ; Virus Replication ; eIF-2 Kinase/antagonists & inhibitors
    Chemical Substances Antiviral Agents ; Interferon-alpha ; RNA, Viral ; Viral Nonstructural Proteins ; eIF-2 Kinase (EC 2.7.11.1) ; NS-5 protein, hepatitis C virus (EC 2.7.7.48) ; RNA-Dependent RNA Polymerase (EC 2.7.7.48)
    Language English
    Publishing date 2020-11-26
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2819778-1
    ISSN 2352-345X ; 2352-345X
    ISSN (online) 2352-345X
    ISSN 2352-345X
    DOI 10.1016/j.jcmgh.2020.11.012
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Cholesterol-modifying drugs in COVID-19.

    Schmidt, Nathalie M / Wing, Peter A C / McKeating, Jane A / Maini, Mala K

    Oxford open immunology

    2020  Volume 1, Issue 1, Page(s) iqaa001

    Abstract: Infection with severe acute respiratory syndrom coronavirus 2 (SARS-CoV-2) is more likely to lead to poor outcomes in the elderly and those with cardiovascular disease, obesity or metabolic syndrome. Here, we consider mechanisms by which dyslipidaemia ... ...

    Abstract Infection with severe acute respiratory syndrom coronavirus 2 (SARS-CoV-2) is more likely to lead to poor outcomes in the elderly and those with cardiovascular disease, obesity or metabolic syndrome. Here, we consider mechanisms by which dyslipidaemia and the use of cholesterol-modifying drugs could influence the virus-host relationship. Cholesterol is essential for the assembly, replication and infectivity of enveloped virus particles; we highlight several cholesterol-modifying drugs with the potential to alter the SARS-CoV-2 life cycle that could be tested in
    Keywords covid19
    Language English
    Publishing date 2020-06-18
    Publishing country England
    Document type Journal Article
    ISSN 2633-6960
    ISSN (online) 2633-6960
    DOI 10.1093/oxfimm/iqaa001
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Hypoxia inducible factors inhibit respiratory syncytial virus infection by modulation of nucleolin expression

    Xiaodong Zhuang / Giulia Gallo / Parul Sharma / Jiyeon Ha / Andrea Magri / Helene Borrmann / James M. Harris / Senko Tsukuda / Eleanor Bentley / Adam Kirby / Simon de Neck / Hongbing Yang / Peter Balfe / Peter A.C. Wing / David Matthews / Adrian L. Harris / Anja Kipar / James P. Stewart / Dalan Bailey /
    Jane A. McKeating

    iScience, Vol 27, Iss 1, Pp 108763- (2024)

    2024  

    Abstract: Summary: Respiratory syncytial virus (RSV) is a global healthcare problem, causing respiratory illness in young children and elderly individuals. Our knowledge of the host pathways that define susceptibility to infection and disease severity are limited. ...

    Abstract Summary: Respiratory syncytial virus (RSV) is a global healthcare problem, causing respiratory illness in young children and elderly individuals. Our knowledge of the host pathways that define susceptibility to infection and disease severity are limited. Hypoxia inducible factors (HIFs) define metabolic responses to low oxygen and regulate inflammatory responses in the lower respiratory tract. We demonstrate a role for HIFs to suppress RSV entry and RNA replication. We show that hypoxia and HIF prolyl-hydroxylase inhibitors reduce the expression of the RSV entry receptor nucleolin and inhibit viral cell-cell fusion. We identify a HIF regulated microRNA, miR-494, that regulates nucleolin expression. In RSV-infected mice, treatment with the clinically approved HIF prolyl-hydroxylase inhibitor, Daprodustat, reduced the level of infectious virus and infiltrating monocytes and neutrophils in the lung. This study highlights a role for HIF-signalling to limit multiple aspects of RSV infection and associated inflammation and informs future therapeutic approaches for this respiratory pathogen.
    Keywords Molecular biology ; Omics ; Transcriptomics ; Science ; Q
    Subject code 570
    Language English
    Publishing date 2024-01-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Level of Evidence for the Treatment of Chronic Noninsertional Achilles Tendinopathy.

    Peters, Mikaela J / Walsh, Kellen / Day, Chris / Younger, Alastair / Salat, Peter / Penner, Murray / Wing, Kevin / Glazebrook, Mark / Veljkovic, Andrea

    Foot & ankle specialist

    2021  Volume 16, Issue 4, Page(s) 406–426

    Abstract: ... poor evidence (grade C) in support of flexor hallucis longus transfer, longitudinal tenotomy ...

    Abstract Background: Noninsertional Achilles tendinopathy affects both athletes and sedentary individuals, and its incidence is rising. Conservative management is the mainstay of treatment, but a variety of operative techniques have been described to treat recalcitrant cases. We seek to outline the current available evidence for surgical management of noninsertional Achilles tendinopathy.
    Study design and methods: A systematic review was performed using the MEDLINE and EMBASE databases, and all articles were reviewed by at least 2 authors. Each article was assigned a level of evidence in accordance with the standards of
    Results and conclusion: A total of 46 articles met inclusion and exclusion criteria. There is fair evidence (grade B) in support of open debridement with 1 level II study, 1 level III study, and 8 level IV studies. There is fair evidence (grade B) in support of arthroscopic or minimally invasive surgical techniques. There is poor evidence (grade C) in support of flexor hallucis longus transfer, longitudinal tenotomy, peritenolysis, gastrocnemius recession, and plantaris excision. There is insufficient evidence (grade I) to provide a recommendation about other surgical treatment methods for noninsertional Achilles tendinopathy.
    MeSH term(s) Humans ; Achilles Tendon/surgery ; Tendinopathy/surgery ; Tenotomy/methods ; Minimally Invasive Surgical Procedures ; Muscle, Skeletal/surgery
    Language English
    Publishing date 2021-03-22
    Publishing country United States
    Document type Systematic Review ; Journal Article ; Review
    ZDB-ID 2488579-4
    ISSN 1938-7636 ; 1938-6400
    ISSN (online) 1938-7636
    ISSN 1938-6400
    DOI 10.1177/19386400211001261
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article: Genetic parameters for residual feed intake, methane emissions, and body composition in New Zealand maternal sheep.

    Johnson, Patricia L / Hickey, Sharon / Knowler, Kevin / Wing, Janine / Bryson, Brooke / Hall, Melanie / Jonker, Arjan / Janssen, Peter H / Dodds, Ken G / McEwan, John C / Rowe, Suzanne J

    Frontiers in genetics

    2022  Volume 13, Page(s) 911639

    Abstract: There is simultaneous interest in improving the feed efficiency of ruminant livestock and reducing methane ( ... ...

    Abstract There is simultaneous interest in improving the feed efficiency of ruminant livestock and reducing methane (CH
    Language English
    Publishing date 2022-08-16
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2606823-0
    ISSN 1664-8021
    ISSN 1664-8021
    DOI 10.3389/fgene.2022.911639
    Database MEDical Literature Analysis and Retrieval System OnLINE

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