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Ahmed, Shereen, Behzad Anwar und Tabassum Iqbal. „Language Contact: A Study of Syllabic Change of English Borrowed Words in Urdu“. International Journal of English Linguistics 8, Nr. 2 (23.12.2017): 140. http://dx.doi.org/10.5539/ijel.v8n2p140.
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This paper aims to describe the syllabic changes in those words which Urdu has borrowed from the English language. The changes are observed by exploring the sequence of sounds present in the syllables of English words. The results are presented on the basis of collection of English words taken from Urdu lexicon. The syllable templates that undergo change during the process of Urdu syllabification are: CCV, CVC, CVCC, CCVC, CCVCC, CVVC, CVVVC, CCCV, CCCVC, and CCCVCC. The current study has formulated some specific generalizations and constraints on the basis of which these changes occur. The study has deduced two processes of epenthesis and replacement/substitution which trigger these changes with respect to the phonological rules and phonotactic constraints of the Urdu language.
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Hu, Jie-Li, und Ai-Long Huang. „Dynamics of Hepatitis B Virus Covalently Closed Circular DNA: A Mini-Review“. Microorganisms 11, Nr. 3 (27.02.2023): 600. http://dx.doi.org/10.3390/microorganisms11030600.
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Eradication of cccDNA is an ideal goal of chronic hepatitis B (CHB) therapy. Understanding the changes in the cccDNA pool during therapy provides a basis for developing CHB treatment strategies. On the other hand, the shift in the balance of the cccDNA pool following therapies allowed researchers to investigate the dynamics of cccDNA. Central to the description of cccDNA dynamics is a parameter called cccDNA half-life. CccDNA half-life is not an intrinsic property of cccDNA molecules, but a description of an observed phenomenon characterized by cccDNA pool decline. Since cccDNA has to be in the nuclei of host cells to function, the half-life of cccDNA is determined by the state and destiny of the host cells. The major factors that drive cccDNA decay include noncytopathic effects and hepatocyte turnover (death and division). In some cases, the determining factor is not the half-life of cccDNA itself, but rather the half-life of the hepatocyte. The main purpose of this review is to analyze the major factors affecting cccDNA half-life and determine the areas requiring further study. In addition, the discrepancy in cccDNA half-life between short-term and long-term nucleot(s)ide analog (NUC) therapy was reported. Hypotheses were proposed to explain the multi-phasic decline of cccDNA during NUC therapy, and a framework based on cccDNA dynamics was suggested for the consideration of various anti-HBV strategies.
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Hsu, Chao-Wei, Yu-De Chu, Ming-Wei Lai, Chih-Lang Lin, Kung-Hao Liang, Yang-Hsiang Lin und Chau-Ting Yeh. „Hepatitis B Virus Covalently Closed Circular DNA Predicts Postoperative Liver Cancer Metastasis Independent of Virological Suppression“. Cancers 13, Nr. 3 (31.01.2021): 538. http://dx.doi.org/10.3390/cancers13030538.
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New antiviral therapies against hepatitis B virus (HBV) focus on the elimination of covalently closed circular DNA (cccDNA). However, traditional cccDNA-specific quantitative PCR (qPCR) has a narrow effective range, hindering a reliable comparison between the levels of biopsy-derived cccDNAs. Collaterally, the prognostic role of cccDNA in HBV-related hepatocellular carcinoma (HCC) cannot be clearly defined. Here, we developed a peptide nucleic acid (PNA)-clamping qPCR method to provide a wider range of specific cccDNA quantification (up to 5 logs of effective range). Extrachromosomal DNA was extracted from para-neoplastic tissues for cccDNA quantification. In total, 350 HBV-related HCC patients were included for an outcome analysis. Without differential pre-dilution, cccDNA levels in para-neoplastic liver tissues were determined, ranging from < 2 × 103 to 123.0 × 106 copies/gram. The multivariate linear regression analysis showed that cccDNA was independently correlated with the HBV e antigen (p < 0.001) and serum HBV-DNA levels (p = 0.012). The Cox proportional hazard model analysis showed that cccDNA independently predicted overall survival (p = 0.003) and extrahepatic metastasis-free survival (p = 0.001). In virologically suppressed HCC patients, cccDNA still effectively predicted intrahepatic recurrence-free (p = 0.003) and extrahepatic metastasis-free (p = 0.009) survivals. In conclusion, cccDNA independently predicted postoperative extrahepatic metastasis-free survival.
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Cai, Dawei, Courtney Mills, Wenquan Yu, Ran Yan, Carol E. Aldrich, Jeffry R. Saputelli, William S. Mason et al. „Identification of Disubstituted Sulfonamide Compounds as Specific Inhibitors of Hepatitis B Virus Covalently Closed Circular DNA Formation“. Antimicrobial Agents and Chemotherapy 56, Nr. 8 (29.05.2012): 4277–88. http://dx.doi.org/10.1128/aac.00473-12.
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ABSTRACTHepatitis B virus (HBV) covalently closed circular DNA (cccDNA) plays a central role in viral infection and persistence and is the basis for viral rebound after the cessation of therapy, as well as the elusiveness of a cure even after extended treatment. Therefore, there is an urgent need for the development of novel therapeutic agents that directly target cccDNA formation and maintenance. By employing an innovative cell-based cccDNA assay in which secreted HBV e antigen is a cccDNA-dependent surrogate, we screened an in-house small-molecule library consisting of 85,000 drug-like compounds. Two structurally related disubstituted sulfonamides (DSS), termed CCC-0975 and CCC-0346, emerged and were confirmed as inhibitors of cccDNA production, with low micromolar 50% effective concentrations (EC50s) in cell culture. Further mechanistic studies demonstrated that DSS compound treatment neither directly inhibited HBV DNA replication in cell culture nor reduced viral polymerase activity in thein vitroendogenous polymerase assay but synchronously reduced the levels of HBV cccDNA and its putative precursor, deproteinized relaxed circular DNA (DP-rcDNA). However, DSS compounds did not promote the intracellular decay of HBV DP-rcDNA and cccDNA, suggesting that the compounds interfere primarily with rcDNA conversion into cccDNA. In addition, we demonstrated that CCC-0975 was able to reduce cccDNA biosynthesis in duck HBV-infected primary duck hepatocytes. This is the first attempt, to our knowledge, to identify small molecules that target cccDNA formation, and DSS compounds thus potentially serve as proof-of-concept drug candidates for development into therapeutics to eliminate cccDNA from chronic HBV infection.
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Mohd-Ismail, Lim, Gunaratne und Tan. „Mapping the Interactions of HBV cccDNA with Host Factors“. International Journal of Molecular Sciences 20, Nr. 17 (01.09.2019): 4276. http://dx.doi.org/10.3390/ijms20174276.
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Hepatitis B virus (HBV) infection is a major health problem affecting about 300 million people globally. Although successful administration of a prophylactic vaccine has reduced new infections, a cure for chronic hepatitis B (CHB) is still unavailable. Current anti-HBV therapies slow down disease progression but are not curative as they cannot eliminate or permanently silence HBV covalently closed circular DNA (cccDNA). The cccDNA minichromosome persists in the nuclei of infected hepatocytes where it forms the template for all viral transcription. Interactions between host factors and cccDNA are crucial for its formation, stability, and transcriptional activity. Here, we summarize the reported interactions between HBV cccDNA and various host factors and their implications on HBV replication. While the virus hijacks certain cellular processes to complete its life cycle, there are also host factors that restrict HBV infection. Therefore, we review both positive and negative regulation of HBV cccDNA by host factors and the use of small molecule drugs or sequence-specific nucleases to target these interactions or cccDNA directly. We also discuss several reporter-based surrogate systems that mimic cccDNA biology which can be used for drug library screening of cccDNA-targeting compounds as well as identification of cccDNA-related targets.
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Allweiss, Lena, Tassilo Volz, Katja Giersch, Janine Kah, Giuseppina Raffa, Joerg Petersen, Ansgar W. Lohse et al. „Proliferation of primary human hepatocytes and prevention of hepatitis B virus reinfection efficiently deplete nuclear cccDNA in vivo“. Gut 67, Nr. 3 (20.04.2017): 542–52. http://dx.doi.org/10.1136/gutjnl-2016-312162.
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ObjectiveThe stability of the covalently closed circular DNA (cccDNA) in nuclei of non-dividing hepatocytes represents a key determinant of HBV persistence. Contrarily, studies with animal hepadnaviruses indicated that hepatocyte turnover can reduce cccDNA loads but knowledge on the proliferative capacity of HBV-infected primary human hepatocytes (PHHs) in vivo and the fate of cccDNA in dividing PHHs is still lacking. This study aimed to determine the impact of human hepatocyte division on cccDNA stability in vivo.MethodsPHH proliferation was triggered by serially transplanting hepatocytes from HBV-infected humanised mice into naïve recipients. Cell proliferation and virological changes were assessed by quantitative PCR, immunofluorescence and RNA in situ hybridisation. Viral integrations were analysed by gel separation and deep sequencing.ResultsPHH proliferation strongly reduced all infection markers, including cccDNA (median 2.4 log/PHH). Remarkably, cell division appeared to cause cccDNA dilution among daughter cells and intrahepatic cccDNA loss. Nevertheless, HBV survived in sporadic non-proliferating human hepatocytes, so that virological markers rebounded as hepatocyte expansion relented. This was due to reinfection of quiescent PHHs since treatment with the entry inhibitor myrcludex-B or nucleoside analogues blocked viral spread and intrahepatic cccDNA accumulation. Viral integrations were detected both in donors and recipient mice but did not appear to contribute to antigen production.ConclusionsWe demonstrate that human hepatocyte division even without involvement of cytolytic mechanisms triggers substantial cccDNA loss. This process may be fundamental to resolve self-limiting acute infection and should be considered in future therapeutic interventions along with entry inhibition strategies.
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Chou, Yu-Chi, King-Song Jeng, Mong-Liang Chen, Hsiao-Hui Liu, Tzu-Ling Liu, Ya-Ling Chen, Yu-Chih Liu, Cheng-po Hu und Chungming Chang. „Evaluation of Transcriptional Efficiency of Hepatitis B Virus Covalently Closed Circular DNA by Reverse Transcription-PCR Combined with the Restriction Enzyme Digestion Method“. Journal of Virology 79, Nr. 3 (01.02.2005): 1813–23. http://dx.doi.org/10.1128/jvi.79.3.1813-1823.2005.
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ABSTRACT Virus persistence in chronic hepatitis B patients is due to the sustaining level of covalently closed circular DNA (cccDNA) within the nuclei of infected hepatocytes. In this study, we used a modified 1.3-fold hepatitis B virus (HBV) genome, with a BclI genetic marker embedded in the redundancy region, to examine the transcriptional activity of cccDNA and the effect of the HBx protein on transcriptional regulation. After harvesting total RNA from transfected cells or stable lines, we specifically identified and monitored the transcripts from cccDNA by using reverse transcription-PCR (RT-PCR) combined with the restriction enzyme digestion method. In this approach, we have found that (i) RT-PCR combined with detection of the BclI marker is a highly specific method for distinguishing cccDNA-derived transcripts from the original integrated viral genome, (ii) the transcriptional ability of cccDNA was less efficient than that from the integrated viral genome, and (iii) the transcriptional activity of cccDNA was significantly regulated by the HBx protein, a potential transcription activator. In conclusion, we provided a tool with which to elucidate the transcriptional regulation of cccDNA and clarified the transcriptional regulation mechanism of HBx on cccDNA. The results obtained may be helpful in the development of a clinical intervention for patients with chronic HBV infections.
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Doan, Phuong Thi Bich, Kouki Nio, Tetsuro Shimakami, Kazuyuki Kuroki, Ying-Yi Li, Saiho Sugimoto, Hideo Takayama et al. „Super-Resolution Microscopy Analysis of Hepatitis B Viral cccDNA and Host Factors“. Viruses 15, Nr. 5 (16.05.2023): 1178. http://dx.doi.org/10.3390/v15051178.
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Infection with hepatitis B virus (HBV) cannot be cured completely because of the persistence of covalently closed circular DNA (cccDNA). We previously found that the host gene dedicator of cytokinesis 11 (DOCK11) was required for HBV persistence. In this study, we further investigated the mechanism that links DOCK11 to other host genes in the regulation of cccDNA transcription. cccDNA levels were determined by quantitative real-time polymerase chain reaction (qPCR) and fluorescence in situ hybridization (FISH) in stable HBV-producing cell lines and HBV-infected PXB-cells®. Interactions between DOCK11 and other host genes were identified by super-resolution microscopy, immunoblotting, and chromatin immunoprecipitation. FISH facilitated the subcellular localization of key HBV nucleic acids. Interestingly, although DOCK11 partially colocalized with histone proteins, such as H3K4me3 and H3K27me3, and nonhistone proteins, such as RNA Pol II, it played limited roles in histone modification and RNA transcription. DOCK11 was functionally involved in regulating the subnuclear distribution of host factors and/or cccDNA, resulting in an increase in cccDNA closely located to H3K4me3 and RNA Pol II for activating cccDNA transcription. Thus, it was suggested that the association of cccDNA-bound Pol II and H3K4me3 required the assistance of DOCK11. DOCK11 facilitated the association of cccDNA with H3K4me3 and RNA Pol II.
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Yu, Hai-Bo, Sheng-Tao Cheng, Fang Ren, Yong Chen, Xiao-Feng Shi, Vincent Kam Wai Wong, Betty Yuen Kwan Law et al. „SIRT7 restricts HBV transcription and replication through catalyzing desuccinylation of histone H3 associated with cccDNA minichromosome“. Clinical Science 135, Nr. 12 (Juni 2021): 1505–22. http://dx.doi.org/10.1042/cs20210392.
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Abstract Chronic hepatitis B virus (HBV) infection is a significant public health burden worldwide. HBV covalently closed circular DNA (cccDNA) organized as a minichromosome in nucleus is responsible for viral persistence and is the key obstacle for a cure of chronic hepatitis B (CHB). Recent studies suggest cccDNA transcription is epigenetically regulated by histone modifications, especially histone acetylation and methylation. In the present study, we identified transcriptionally active histone succinylation (H3K122succ) as a new histone modification on cccDNA minichromosome by using cccDNA ChIP-Seq approach. Silent mating type information regulation 2 homolog 7 (SIRT7), as an NAD+-dependent histone desuccinylase, could bind to cccDNA through interaction with HBV core protein where it catalyzed histone 3 lysine 122 (H3K122) desuccinylation. Moreover, SIRT7 acts cooperatively with histone methyltransferase, suppressor of variegation 3–9 homolog 1 (SUV39H1) and SET domain containing 2 (SETD2) to induce silencing of HBV transcription through modulation of chromatin structure. Our data improved the understanding of histone modifications of the cccDNA minichromosome, thus transcriptional silencing of cccDNA may represent a novel antiviral strategy for the prevention or treatment of HBV infection.
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Marchetti, Alexander L., und Haitao Guo. „New Insights on Molecular Mechanism of Hepatitis B Virus Covalently Closed Circular DNA Formation“. Cells 9, Nr. 11 (06.11.2020): 2430. http://dx.doi.org/10.3390/cells9112430.
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The chronic factor of the Hepatitis B Virus (HBV), specifically the covalently closed circular DNA (cccDNA), is a highly stable and active viral episomal genome established in the livers of chronic hepatitis B patients as a constant source of disease. Being able to target and eliminate cccDNA is the end goal for a genuine cure for HBV. Yet how HBV cccDNA is formed from the viral genomic relaxed circular DNA (rcDNA) and by what host factors had been long-standing research questions. It is generally acknowledged that HBV hijacks cellular functions to turn the open circular DNA conformation of rcDNA into cccDNA through DNA repair mechanisms. With great efforts from the HBV research community, there have been several recent leaps in our understanding of cccDNA formation. It is our goal in this review to analyze the recent reports showing evidence of cellular factor’s involvement in the molecular pathway of cccDNA biosynthesis.
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Addison, William R., Kathie-Anne Walters, Winnie W. S. Wong, John S. Wilson, Danuta Madej, Lawrence D. Jewell und D. Lorne J. Tyrrell. „Half-Life of the Duck Hepatitis B Virus Covalently Closed Circular DNA Pool In Vivo following Inhibition of Viral Replication“. Journal of Virology 76, Nr. 12 (15.06.2002): 6356–63. http://dx.doi.org/10.1128/jvi.76.12.6356-6363.2002.
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ABSTRACT Covalently closed circular DNA (cccDNA) is a crucial intermediate in the replication of hepadnaviruses. We inhibited the replication of duck hepatitis B virus in congenitally infected ducks with a combination of lamivudine and a dideoxyguanosine prodrug. Inhibition of viral replication should prevent renewal of the cccDNA pool, and its decay was measured in liver biopsy samples collected over a 5-month period. In three ducks, the cccDNA pools declined exponentially, with half-lives ranging from 35 to 57 days. In two others, the pools declined exponentially for about 70 days but then stabilized at about 6 copies/diploid genome. The selection of drug-resistant virus mutants is an unlikely explanation for this unexpected stabilization of cccDNA levels. Liver sections stained for the cell division marker PCNA showed that animals in which cccDNA loss was continuous had significantly greater numbers of PCNA-positive nuclei than did those animals in which cccDNA levels had plateaued.
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Zhu, Yuao, Toshiki Yamamoto, John Cullen, Jeffry Saputelli, Carol E. Aldrich, Darren S. Miller, Samuel Litwin, Phillip A. Furman, Allison R. Jilbert und William S. Mason. „Kinetics of Hepadnavirus Loss from the Liver during Inhibition of Viral DNA Synthesis“. Journal of Virology 75, Nr. 1 (01.01.2001): 311–22. http://dx.doi.org/10.1128/jvi.75.1.311-322.2001.
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ABSTRACT Hepadnaviruses replicate by reverse transcription, which takes place in the cytoplasm of the infected hepatocyte. Viral RNAs, including the pregenome, are transcribed from a covalently closed circular (ccc) viral DNA that is found in the nucleus. Inhibitors of the viral reverse transcriptase can block new DNA synthesis but have no direct effect on the up to 50 or more copies of cccDNA that maintain the infected state. Thus, during antiviral therapy, the rates of loss of cccDNA, infected hepatocytes (1 or more molecules of cccDNA), and replicating DNAs may be quite different. In the present study, we asked how these losses compared when woodchucks chronically infected with woodchuck hepatitis virus were treated with L-FMAU [1-(2-fluoro-5-methyl-β-l-arabinofuranosyl) uracil], an inhibitor of viral DNA synthesis. Viremia was suppressed for at least 8 months, after which drug-resistant virus began replicating to high titers. In addition, replicating viral DNAs were virtually absent from the liver after 6 weeks of treatment. In contrast, cccDNA declined more slowly, consistent with a half-life of ∼33 to 50 days. The loss of cccDNA was comparable to that expected from the estimated death rate of hepatocytes in these woodchucks, suggesting that death of infected cells was one of the major routes for elimination of cccDNA. However, the decline in the actual number of infected hepatocytes lagged behind the decline in cccDNA, so that the average cccDNA copy number in infected cells dropped during the early phase of therapy. This observation was consistent with the possibility that some fraction of cccDNA was distributed to daughter cells in those infected hepatocytes that passed through mitosis.
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Mendenhall, Megan A., Xupeng Hong und Jianming Hu. „Hepatitis B Virus Capsid: The Core in Productive Entry and Covalently Closed Circular DNA Formation“. Viruses 15, Nr. 3 (28.02.2023): 642. http://dx.doi.org/10.3390/v15030642.
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Hepatitis B virus (HBV) relies on the core protein (HBc) to establish productive infection, as defined by the formation of the covalently closed circularized DNA (cccDNA), as well as to carry out almost every step of the lifecycle following cccDNA formation. Multiple copies of HBc form an icosahedral capsid shell that encapsidates the viral pregenomic RNA (pgRNA) and facilitates the reverse transcription of pgRNA to a relaxed circular DNA (rcDNA) within the capsid. During infection, the complete HBV virion, which contains an outer envelope layer in addition to the internal nucleocapsid containing rcDNA, enters human hepatocytes via endocytosis and traffics through the endosomal compartments and the cytosol to deliver its rcDNA to the nucleus to produce cccDNA. In addition, progeny rcDNA, newly formed in cytoplasmic nucleocapsids, is also delivered to the nucleus in the same cell to form more cccDNA in a process called intracellular cccDNA amplification or recycling. Here, we focus on recent evidence demonstrating differential effects of HBc in affecting cccDNA formation during de novo infection vs. recycling, obtained using HBc mutations and small molecule inhibitors. These results implicate a critical role of HBc in determining HBV trafficking during infection, as well as in nucleocapsid disassembly (uncoating) to release rcDNA, events essential for cccDNA formation. HBc likely functions in these processes via interactions with host factors, which contributes critically to HBV host tropism. A better understanding of the roles of HBc in HBV entry, cccDNA formation, and host species tropism should accelerate ongoing efforts to target HBc and cccDNA for the development of an HBV cure and facilitate the establishment of convenient animal models for both basic research and drug development.
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Schopow, Nikolas, Georg Osterhoff, Nikolaus von Dercks, Felix Girrbach, Christoph Josten, Sebastian Stehr und Pierre Hepp. „Central COVID-19 Coordination Centers in Germany: Description, Economic Evaluation, and Systematic Review“. JMIR Public Health and Surveillance 7, Nr. 11 (18.11.2021): e33509. http://dx.doi.org/10.2196/33509.
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Background During the COVID-19 pandemic, Central COVID-19 Coordination Centers (CCCCs) have been established at several hospitals across Germany with the intention to assist local health care professionals in efficiently referring patients with suspected or confirmed SARS-CoV-2 infection to regional hospitals and therefore to prevent the collapse of local health system structures. In addition, these centers coordinate interhospital transfers of patients with COVID-19 and provide or arrange specialized telemedical consultations. Objective This study describes the establishment and management of a CCCC at a German university hospital. Methods We performed economic analyses (cost, cost-effectiveness, use, and utility) according to the CHEERS (Consolidated Health Economic Evaluation Reporting Standards) criteria. Additionally, we conducted a systematic review to identify publications on similar institutions worldwide. The 2 months with the highest local incidence of COVID-19 cases (December 2020 and January 2021) were considered. Results During this time, 17.3 requests per day were made to the CCCC regarding admission or transfer of patients with COVID-19. The majority of requests were made by emergency medical services (601/1068, 56.3%), patients with an average age of 71.8 (SD 17.2) years were involved, and for 737 of 1068 cases (69%), SARS-CoV-2 had already been detected by a positive polymerase chain reaction test. In 59.8% (639/1068) of the concerned patients, further treatment by a general practitioner or outpatient presentation in a hospital could be initiated after appropriate advice, 27.2% (291/1068) of patients were admitted to normal wards, and 12.9% (138/1068) were directly transmitted to an intensive care unit. The operating costs of the CCCC amounted to more than €52,000 (US $60,031) per month. Of the 334 patients with detected SARS-CoV-2 who were referred via EMS or outpatient physicians, 302 (90.4%) were triaged and announced in advance by the CCCC. No other published economic analysis of COVID-19 coordination or management institutions at hospitals could be found. Conclusions Despite the high cost of the CCCC, we were able to show that it is a beneficial concept to both the providing hospital and the public health system. However, the most important benefits of the CCCC are that it prevents hospitals from being overrun by patients and that it avoids situations in which physicians must weigh one patient’s life against another’s.
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Schopow, Nikolas, Georg Osterhoff, Nikolaus von Dercks, Felix Girrbach, Christoph Josten, Sebastian Stehr und Pierre Hepp. „Central COVID-19 Coordination Centers in Germany: Description, Economic Evaluation, and Systematic Review“. JMIR Public Health and Surveillance 7, Nr. 11 (18.11.2021): e33509. http://dx.doi.org/10.2196/33509.
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Background During the COVID-19 pandemic, Central COVID-19 Coordination Centers (CCCCs) have been established at several hospitals across Germany with the intention to assist local health care professionals in efficiently referring patients with suspected or confirmed SARS-CoV-2 infection to regional hospitals and therefore to prevent the collapse of local health system structures. In addition, these centers coordinate interhospital transfers of patients with COVID-19 and provide or arrange specialized telemedical consultations. Objective This study describes the establishment and management of a CCCC at a German university hospital. Methods We performed economic analyses (cost, cost-effectiveness, use, and utility) according to the CHEERS (Consolidated Health Economic Evaluation Reporting Standards) criteria. Additionally, we conducted a systematic review to identify publications on similar institutions worldwide. The 2 months with the highest local incidence of COVID-19 cases (December 2020 and January 2021) were considered. Results During this time, 17.3 requests per day were made to the CCCC regarding admission or transfer of patients with COVID-19. The majority of requests were made by emergency medical services (601/1068, 56.3%), patients with an average age of 71.8 (SD 17.2) years were involved, and for 737 of 1068 cases (69%), SARS-CoV-2 had already been detected by a positive polymerase chain reaction test. In 59.8% (639/1068) of the concerned patients, further treatment by a general practitioner or outpatient presentation in a hospital could be initiated after appropriate advice, 27.2% (291/1068) of patients were admitted to normal wards, and 12.9% (138/1068) were directly transmitted to an intensive care unit. The operating costs of the CCCC amounted to more than €52,000 (US $60,031) per month. Of the 334 patients with detected SARS-CoV-2 who were referred via EMS or outpatient physicians, 302 (90.4%) were triaged and announced in advance by the CCCC. No other published economic analysis of COVID-19 coordination or management institutions at hospitals could be found. Conclusions Despite the high cost of the CCCC, we were able to show that it is a beneficial concept to both the providing hospital and the public health system. However, the most important benefits of the CCCC are that it prevents hospitals from being overrun by patients and that it avoids situations in which physicians must weigh one patient’s life against another’s.
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Brezgin, S. A., A. P. Kostyusheva, V. N. Simirsky, E. V. Volchkova, D. S. Chistyakov, D. S. Kostyushev und V. P. Chulanov. „Suppression of hepatitis b virus by a combined activity of CRISPR/Cas9 and HBx proteins“. Russian Journal of Infection and Immunity 9, Nr. 3-4 (15.11.2019): 476–84. http://dx.doi.org/10.15789/2220-7619-2019-3-4-476-484.
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Chronic hepatitis B is a severe liver disease associated with persistent infection with hepatitis B virus. According to recent estimations, 250 million people in the world are chronically infected, including 3 million chronically infected people in Russia. Antiviral therapeutics (nucleos(t)ide analogues and PEGylated interferon) suppress viral transcription and replication, but do not eliminate the virus from infected cells. The key reason for HBV persistency is a stable form of the viral genome (covalently closed circular DNA, cccDNA) that exists as a minichromosome protected from novel cccDNA-targeting therapeutics. Novel therapeutic approaches aimed at elimination or inactivation of cccDNA are urgently needed. CRISPR/Cas9 systems induce double strand breaks in target sites of DNA sequences. Experiments with CRISPR/Cas9 demonstrated high antiviral activity and efficient cleavage of cccDNA, but a small part of cccDNA pool remains intact. One of the main reasons of incomplete cccDNA elimination might be the structural organization of cccDNA, which persists in a heterochromatinized, very compacted form and is not be accessible to CRISPR/Cas9 systems. Viral protein HBx unwinds cccDNA and regulates cccDNA epigenetically by recruiting transcription-remodeling factors. In this work, we analyzed effects of CRISPR/Cas9 in combination with an HBxencoding plasmid or plasmids encoding mutant forms of HBx (HBxMut, which does not interact with pro-apoptotic factors Bcl-2 и Bcl-xL, and HBxNesm is localized exclusively in the nucleus and does not generate reactive oxygen species and double strand breaks in the genome). We showed that HBx improves CRISPR/Cas9 efficiency, decreasing pregenomic RNA transcription level over 98%. Moreover, we analyzed optimal ratios of plasmids encoding CRISPR/ Cas9 and HBx proteins for better antiviral efficacy. Furthermore, we discovered that HBx proteins do not have an effect on proliferation and viability of the transfected cells. In conclusion, CRISPR/Cas9 with HBx proteins exhibit high antiviral effect.
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Wang, Qin, Wei Luan, M. Isabel Fiel, Sima Blank, Ki Won Kim und Spiros P. Hiotis. „Quantitative analysis of intrahepatic hepatitis B (HBV) DNA and cccDNA and their impact on survival posthepatectomy in HBV-associated hepatocellular carcinoma (HCC) patients.“ Journal of Clinical Oncology 30, Nr. 15_suppl (20.05.2012): e14583-e14583. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e14583.
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e14583 Background: Little is known about the prognostic significance of total intrahepatic HBV DNA (ihHBV DNA) and cccDNA, a stable episome that accumulates in the nuclei and serves as the template for viral replication. This study aims to quantitate ihHBV DNA and cccDNA in the non-neoplastic liver and to assess their impact on prognosis in HBV-HCC patients. Methods: 111 patients, many on HBV antivirals, who underwent liver resection for HBV-HCC from 1991 to 2008 were assessed by real time PCR for ihHBV DNA, cccDNA, and albumin. Liver fibrosis and necroinflammation was assessed using the modified Ishak method. Independent variables associated with survival were analyzed using multivariate Cox regression model, with a median follow up for survivors of 52 months. Results: Serum HBV DNA was detectable in only 42% of patients, but 106 patients (95%) had detectable ihHBV DNA (median: 0.018copy/hepatocyte); and 89 patients (80%) had detectable cccDNA (0.00058 copy/hepatocyte). Median cccDNA/ihHBV DNA ratio was 0.019. ihHBV DNA correlated with histologic activity index (p = 0.04) and serum ALT (p = 0.004). Patients in the lowest quartile of cccDNA/ihHBV DNA ratio (<0.0032) trended towards poor overall 5-year survival by univariate analysis (p = 0.09), with higher mortality at 2 years (89% vs. 45%, p = 0.03). In multivariate analysis, AFP > 20, Ishak fibrosis stage 6 (established cirrhosis), cccDNA/ihHBV DNA < 0.0032, and large tumor diameter were independently associated with poor overall survival (Table). Conclusions: ihHBV DNA levels were associated with severity of liver necroinflammation and injury. ihHBV DNA and cccDNA levels were not associated with survival; rather, low proportion of total HBV DNA in the form of cccDNA was independently associated with poor overall survival. Thus, viral behavior at the time of liver resection influences clinical outcome for HBV-HCC patients. [Table: see text]
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Scott, A. P., und L. Radom. „Are cumulenones kinked? A systematic high-level ab initio study of H 2 CCCO, H 2 CCCCO and H 2 CCCCCO“. Journal of Molecular Structure 556, Nr. 1-3 (Dezember 2000): 253–61. http://dx.doi.org/10.1016/s0022-2860(00)00640-2.
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Diogo Dias, João, Nazim Sarica und Christine Neuveut. „Early Steps of Hepatitis B Life Cycle: From Capsid Nuclear Import to cccDNA Formation“. Viruses 13, Nr. 5 (26.04.2021): 757. http://dx.doi.org/10.3390/v13050757.
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Hepatitis B virus (HBV) remains a major public health concern, with more than 250 million chronically infected people who are at high risk of developing liver diseases, including cirrhosis and hepatocellular carcinoma. Although antiviral treatments efficiently control virus replication and improve liver function, they cannot cure HBV infection. Viral persistence is due to the maintenance of the viral circular episomal DNA, called covalently closed circular DNA (cccDNA), in the nuclei of infected cells. cccDNA not only resists antiviral therapies, but also escapes innate antiviral surveillance. This viral DNA intermediate plays a central role in HBV replication, as cccDNA is the template for the transcription of all viral RNAs, including pregenomic RNA (pgRNA), which in turn feeds the formation of cccDNA through a step of reverse transcription. The establishment and/or expression of cccDNA is thus a prime target for the eradication of HBV. In this review, we provide an update on the current knowledge on the initial steps of HBV infection, from the nuclear import of the nucleocapsid to the formation of the cccDNA.
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Zhang, Xiangying, Yuan Tian, Ling Xu, Zihao Fan, Yaling Cao, Yingmin Ma, Hao Li und Feng Ren. „CRISPR/Cas13-assisted hepatitis B virus covalently closed circular DNA detection“. Hepatology International 16, Nr. 2 (17.03.2022): 306–15. http://dx.doi.org/10.1007/s12072-022-10311-0.
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Abstract Background and aims The formation of an intranuclear pool of covalently closed circular DNA (cccDNA) in the liver is the main cause of persistent hepatitis B virus (HBV) infection. Here, we established highly sensitive and specific methods to detect cccDNA based on CRISPR-Cas13a technology. Methods We used plasmid-safe ATP-dependent DNase (PSAD) enzymes and HindIII to digest loose circle rcDNA and double-stranded linear DNA, amplify specific HBV cccDNA fragments by rolling circle amplification (RCA) and PCR, and detect the target gene using CRISPR-Cas13a technology. The CRISPR-Cas13a-based assay for the detection of cccDNA was further clinically validated using HBV-related liver tissues, plasma, whole blood and peripheral blood mononuclear cells (PBMCs). Results Based on the sample pretreatment step, the amplification step and the detection step, we established a new CRISPR-Cas13a-based assay for the detection of cccDNA. After the amplification of RCA and PCR, 1 copy/μl HBV cccDNA could be detected by CRISPR/Cas13-assisted fluorescence readout. We used ddPCR, qPCR, RCA-qPCR, PCR-CRISPR and RCA-PCR-CRISPR methods to detect 20, 4, 18, 14 and 29 positive samples in liver tissue samples from 40 HBV-related patients, respectively. HBV cccDNA was almost completely undetected in the 20 blood samples of HBV patients (including plasma, whole blood and PBMCs) by the above 5 methods. Conclusions We developed a novel CRISPR-based assay for the highly sensitive and specific detection of HBV cccDNA, presenting a promising alternative for accurate detection of HBV infection, antiviral therapy evaluation and treatment guidance.
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Caviglia, Gian Paolo, Angelo Armandi, Chiara Rosso, Davide Giuseppe Ribaldone, Rinaldo Pellicano und Sharmila Fagoonee. „Hepatitis B Core-Related Antigen as Surrogate Biomarker of Intrahepatic Hepatitis B Virus Covalently-Closed-Circular DNA in Patients with Chronic Hepatitis B: A Meta-Analysis“. Diagnostics 11, Nr. 2 (28.01.2021): 187. http://dx.doi.org/10.3390/diagnostics11020187.
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Hepatitis B virus (HBV) covalently-closed-circular (ccc)DNA is the key molecule responsible for viral persistence within infected hepatocytes. The evaluation of HBV cccDNA is crucial for the management of patients with chronic HBV infection and for the personalization of treatment. However, the need for liver biopsy is the principal obstacle for the assessment of intrahepatic HBV cccDNA. In the last decade, several studies have investigated the performance of hepatitis B core-related antigen (HBcrAg) as a surrogate of HBV cccDNA amount in the liver. In this meta-analysis, we collected 14 studies (1271 patients) investigating the correlation between serum HBcrAg and intrahepatic HBV cccDNA. Serum HBcrAg showed a high correlation with intrahepatic HBV cccDNA (r = 0.641, 95% confidence interval (CI) 0.510–0.743, p < 0.001). In a head-to-head comparison, we observed that the performance of HBcrAg was significantly superior to that of hepatitis B surface antigen (r = 0.665 vs. r = 0.475, respectively, p < 0.001). Subgroup analysis showed that the correlation between HBcrAg and intrahepatic HBV cccDNA was high, both in hepatitis B e antigen-positive and -negative patients (r = 0.678, 95% CI 0.403–0.840, p < 0.001, and r = 0.578, 95% CI 0.344–0.744, p < 0.001, respectively). In conclusion, the measurement of serum HBcrAg qualifies as a reliable non-invasive surrogate for the assessment of an intrahepatic HBV cccDNA reservoir.
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Shi, Liping, Shaohua Li, Fang Shen, Haodong Li, Shuiming Qian, Daniel H. S. Lee, Jim Z. Wu und Wengang Yang. „Characterization of Nucleosome Positioning in Hepadnaviral Covalently Closed Circular DNA Minichromosomes“. Journal of Virology 86, Nr. 18 (11.07.2012): 10059–69. http://dx.doi.org/10.1128/jvi.00535-12.
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Hepadnaviral covalently closed circular DNA (cccDNA) exists as an episomal minichromosome in the nucleus of virus-infected hepatocytes, and serves as the transcriptional template for the synthesis of viral mRNAs. To obtain insight on the structure of hepadnaviral cccDNA minichromosomes, we utilized ducks infected with the duck hepatitis B virus (DHBV) as a model and determined thein vivonucleosome distribution pattern on viral cccDNA by the micrococcal nuclease (MNase) mapping and genome-wide PCR amplification of isolated mononucleosomal DHBV DNA. Several nucleosome-protected sites in a region of the DHBV genome [nucleotides (nt) 2000 to 2700], known to harbor variouscistranscription regulatory elements, were consistently identified in all DHBV-positive liver samples. In addition, we observed other nucleosome protection sites in DHBV minichromosomes that may vary among individual ducks, but the pattern of MNase mapping in those regions is transmittable from the adult ducks to the newly infected ducklings. These results imply that the nucleosomes along viral cccDNA in the minichromosomes are not random but sequence-specifically positioned. Furthermore, we showed in ducklings that a significant portion of cccDNA possesses a few negative superhelical turns, suggesting the presence of intermediates of viral minichromosomes assembled in the liver, where dynamic hepatocyte growth and cccDNA formation occur. This study supplies the initial framework for the understanding of the overall complete structure of hepadnaviral cccDNA minichromosomes.
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Brezgin, Sergey, Anastasiia Kostyusheva, Ekaterina Bayurova, Ilya Gordeychuk, Maria Isaguliants, Irina Goptar, Anastasiia Nikiforova et al. „Replenishment of Hepatitis B Virus cccDNA Pool Is Restricted by Baseline Expression of Host Restriction Factors In Vitro“. Microorganisms 7, Nr. 11 (06.11.2019): 533. http://dx.doi.org/10.3390/microorganisms7110533.
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Background: Covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV) is the major cause of viral persistence in patients with chronic HBV infection. Understanding the mechanisms underlying stability and persistence of HBV cccDNA in hepatocytes is critical for developing novel therapeutics and managing chronic hepatitis B. In this study, we observed an unexpected increase in HBV cccDNA levels upon suppression of transcription by de novo DNA methyltransferase DNMT3A and uncovered additional mechanisms potentially involved in HBV cccDNA maintenance. Methods: HBV-expressing cell lines were transfected with a DNMT3A-expressing plasmid. Real-time PCR and HBsAg assays were used to assess the HBV replication rate. Cell cycling was analyzed by fluorescent cell sorting. CRISPR/Cas9 was utilized to abrogate expression of APOBEC3A and APOBEC3B. Alterations in the expression of target genes were measured by real-time PCR. Results: Similar to previous studies, HBV replication induced DNMT3A expression, which in turn, led to reduced HBV transcription but elevated HBV cccDNA levels (4- to 6-fold increase). Increased levels of HBV cccDNA were not related to cell cycling, as DNMT3A accelerated proliferation of infected cells and could not contribute to HBV cccDNA expansion by arresting cells in a quiescent state. At the same time, DNMT3A suppressed transcription of innate immunity factors including cytidine deaminases APOBEC3A and APOBEC3B. CRISPR/Cas9-mediated silencing of APOBEC3A and APOBEC3B transcription had minor effects on HBV transcription, but significantly increased HBV cccDNA levels, similar to DNMT3A. In an attempt to further analyze the detrimental effects of HBV and DNMT3A on infected cells, we visualized γ-H2AX foci and demonstrated that HBV inflicts and DNMT3A aggravates DNA damage, possibly by downregulating DNA damage response factors. Additionally, suppression of HBV replication by DNMT3A may be related to reduced ATM/ATR expression. Conclusion: Formation and maintenance of HBV cccDNA pools may be partially suppressed by the baseline expression of host inhibitory factors including APOBEC3A and APOBEC3B. HBV inflicts DNA damage both directly and by inducing DNMT3A expression.
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Gao, Yuhua, Yutang Li, Qinghua Meng, Zhanqing Zhang, Ping Zhao, Qinghua Shang, Yue Li et al. „Serum Hepatitis B Virus DNA, RNA, and HBsAg: Which Correlated Better with Intrahepatic Covalently Closed Circular DNA before and after Nucleos(t)ide Analogue Treatment?“ Journal of Clinical Microbiology 55, Nr. 10 (26.07.2017): 2972–82. http://dx.doi.org/10.1128/jcm.00760-17.
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ABSTRACT The study was designed to investigate whether serum hepatitis B virus (HBV) RNA is a strong surrogate marker for intrahepatic HBV covalently closed circular DNA (cccDNA) compared with serum HBV DNA, hepatitis B surface antigen (HBsAg), and hepatitis B e antigen (HBeAg) in HBeAg-positive chronic hepatitis B (CHB) patients. Serum HBV RNA, HBV DNA, HBsAg, HBeAg, and intrahepatic cccDNA were quantitatively detected at baseline ( n = 82) and 96 weeks ( n = 62) after treatment with nucleos(t)ide analogue (NUC) in HBeAg-positive CHB patients. The correlations among serum HBV RNA, HBV DNA, HBsAg, HBeAg, and intrahepatic cccDNA levels were then statistically analyzed. The results showed that pretreatment intrahepatic cccDNA levels correlated better with serum HBV DNA levels ( r = 0.36, P < 0.01) than with serum HBV RNA levels ( r = 0.25, P = 0.02), whereas no correlations were found between pretreatment intrahepatic cccDNA levels and HBsAg ( r = 0.15, P = 0.17) or HBeAg ( r = 0.07, P = 0.56) levels. At 96 weeks after NUC treatment, intrahepatic cccDNA levels correlated well with HBsAg levels ( r = 0.39, P < 0.01) but not with serum HBV RNA, HBV DNA, and HBeAg levels (all P > 0.05). Besides, the decline in the intrahepatic cccDNA level from baseline to week 96 correlated better with the reduction in the serum HBsAg levels than with the decreases in the levels of the other markers (for the HBsAg decline, r = 0.38, P < 0.01; for the HBV DNA decline, r = 0.35, P = 0.01; for the HBV RNA decline, r = 0.28, P < 0.05; for the HBeAg decline, r = 0.18, P = 0.19). In conclusion, the baseline serum HBV RNA level or its decline after 96 weeks of NUC therapy correlated with the corresponding intrahepatic cccDNA level, while it was less than that seen with serum HBV DNA at baseline and HBsAg (or its decline) at 96 weeks after treatment, respectively.
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Ceyhan, Elvan, John C. Wierman und Pengfei Xiang. „Law of large numbers for a two-dimensional class cover problem“. ESAIM: Probability and Statistics 25 (2021): 376–407. http://dx.doi.org/10.1051/ps/2021013.
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We prove a Law of Large Numbers (LLN) for the domination number of class cover catch digraphs (CCCD) generated by random points in two (or higher) dimensions. DeVinney and Wierman (2002) proved the Strong Law of Large Numbers (SLLN) for the uniform distribution in one dimension, and Wierman and Xiang (2008) extended the SLLN to the case of general distributions in one dimension. In this article, using subadditive processes, we prove a SLLN result for the domination number generated by Poisson points in ℝ2. From this we obtain a Weak Law of Large Numbers (WLLN) for the domination number generated by random points in [0, 1]2 from uniform distribution first, and then extend these result to the case of bounded continuous distributions. We also extend the results to higher dimensions. The domination number of CCCDs and related digraphs have applications in statistical pattern classification and spatial data analysis.
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Bai, Fugui, Yoshihiko Yano, Takumi Fukumoto, Atsushi Takebe, Motofumi Tanaka, Kaori Kuramitsu, Nungki Anggorowati et al. „Quantification of Pregenomic RNA and Covalently Closed Circular DNA in Hepatitis B Virus-Related Hepatocellular Carcinoma“. International Journal of Hepatology 2013 (2013): 1–9. http://dx.doi.org/10.1155/2013/849290.
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Pregenomic RNA (pgRNA) is generated from covalently closed circular DNA (cccDNA) and plays important roles in viral genome amplification and replication. Hepatic pgRNA and cccDNA expression levels indicate viral persistence and replication activity. This study was aimed to measure hepatic pgRNA and cccDNA expression levels in various states of hepatitis B virus (HBV) infection. Thirty-eight hepatocellular carcinoma (HCC) patients, including 14 positive for hepatitis B surface antigen (HBsAg) and 24 negative for HBsAg but positive for anti-hepatitis B core (anti-HBc) antibody, were enrolled in this study. In HBsAg-negative but anti-HBc-positive group, HBV-DNA was detected in 20 of 24 (83%) noncancerous liver tissues for at least two genomic regions based on polymerase chain reaction (PCR) analysis. pgRNA and cccDNA expression levels in occult HBV-infected patients were significantly lower than those in HBsAg-positive patients (P<0.001). pgRNA and cccDNA in cancerous tissues were also detected without significant difference from those in noncancerous tissues. In conclusion, cccDNA and pgRNA are detected and represented HBV replication not only in noncancerous but also in cancerous liver tissues. In addition, the replication is shown in not only patients with HBsAg-positive but also occult HBV-infected patients, suggesting the contribution to HCC development.
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Ligat, Gaëtan, Kaku Goto, Eloi Verrier und Thomas F. Baumert. „Targeting Viral cccDNA for Cure of Chronic Hepatitis B“. Current Hepatology Reports 19, Nr. 3 (10.07.2020): 235–44. http://dx.doi.org/10.1007/s11901-020-00534-w.
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Abstract Purpose of Review Chronic hepatitis B (CHB), caused by hepatitis B virus (HBV), is a major cause of advanced liver disease and hepatocellular carcinoma (HCC) worldwide. HBV replication is characterized by the synthesis of covalently closed circular (ccc) DNA which is not targeted by antiviral nucleos(t)ide analogues (NUCs) the key modality of standard of care. While HBV replication is successfully suppressed in treated patients, they remain at risk for developing HCC. While functional cure, characterized by loss of HBsAg, is the first goal of novel antiviral therapies, curative treatments eliminating cccDNA remain the ultimate goal. This review summarizes recent advances in the discovery and development of novel therapeutic strategies and their impact on cccDNA biology. Recent Findings Within the last decade, substantial progress has been made in the understanding of cccDNA biology including the discovery of host dependency factors, epigenetic regulation of cccDNA transcription and immune-mediated degradation. Several approaches targeting cccDNA either in a direct or indirect manner are currently at the stage of discovery, preclinical or early clinical development. Examples include genome-editing approaches, strategies targeting host dependency factors or epigenetic gene regulation, nucleocapsid modulators and immune-mediated degradation. Summary While direct-targeting cccDNA strategies are still largely at the preclinical stage of development, capsid assembly modulators and immune-based approaches have reached the clinical phase. Clinical trials are ongoing to assess their efficacy and safety in patients including their impact on viral cccDNA. Combination therapies provide additional opportunities to overcome current limitations of individual approaches.
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Wing, Peter AC, Tamara Davenne, Jochen Wettengel, Alvina G. Lai, Xiaodong Zhuang, Anindita Chakraborty, Valentina D’Arienzo et al. „A dual role for SAMHD1 in regulating HBV cccDNA and RT-dependent particle genesis“. Life Science Alliance 2, Nr. 2 (27.03.2019): e201900355. http://dx.doi.org/10.26508/lsa.201900355.
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Chronic hepatitis B is one of the world’s unconquered diseases with more than 240 million infected subjects at risk of developing liver disease and hepatocellular carcinoma. Hepatitis B virus reverse transcribes pre-genomic RNA to relaxed circular DNA (rcDNA) that comprises the infectious particle. To establish infection of a naïve target cell, the newly imported rcDNA is repaired by host enzymes to generate covalently closed circular DNA (cccDNA), which forms the transcriptional template for viral replication. SAMHD1 is a component of the innate immune system that regulates deoxyribonucleoside triphosphate levels required for host and viral DNA synthesis. Here, we show a positive role for SAMHD1 in regulating cccDNA formation, where KO of SAMHD1 significantly reduces cccDNA levels that was reversed by expressing wild-type but not a mutated SAMHD1 lacking the nuclear localization signal. The limited pool of cccDNA in infectedSamhd1KO cells is transcriptionally active, and we observed a 10-fold increase in newly synthesized rcDNA-containing particles, demonstrating a dual role for SAMHD1 to both facilitate cccDNA genesis and to restrict reverse transcriptase-dependent particle genesis.
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Magri, Andrea, James M. Harris, Valentina D’Arienzo, Rosalba Minisini, Frank Jühling, Peter A. C. Wing, Rachele Rapetti et al. „Inflammatory Gene Expression Associates with Hepatitis B Virus cccDNA- but Not Integrant-Derived Transcripts in HBeAg Negative Disease“. Viruses 14, Nr. 5 (17.05.2022): 1070. http://dx.doi.org/10.3390/v14051070.
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Chronic hepatitis B virus (HBV) infection is a global health problem that presents as a spectrum of liver disease, reflecting an interplay between the virus and the host immune system. HBV genomes exist as episomal covalently closed circular DNA (cccDNA) or chromosomal integrants. The relative contribution of these genomes to the viral transcriptome in chronic hepatitis B (CHB) is not well-understood. We developed a qPCR method to estimate the abundance of HBV cccDNA- and integrant-derived viral transcripts and applied this to a cohort of patients diagnosed with CHB in the HBe antigen negative phase of disease. We noted a variable pattern of HBV transcripts from both DNA templates, with preS1/S2 mRNAs predominating and a significant association between increasing age and the expression of integrant-derived mRNAs, but not with inflammatory status. In contrast, cccDNA-derived transcripts were associated with markers of liver inflammation. Analysis of the inflammatory hepatic transcriptome identified 24 genes significantly associated with cccDNA transcriptional activity. Our study uncovers an immune gene signature that associates with HBV cccDNA transcription and increases our understanding of viral persistence.
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YU, M. M., X. J. GU, Y. XIA, G. J. WANG, N. Y. KAN, H. X. JIANG, K. H. WU, Y. JI und L. L. JU. „Relationship between HBV cccDNA expression in the human ovary and vertical transmission of HBV“. Epidemiology and Infection 140, Nr. 8 (17.10.2011): 1454–60. http://dx.doi.org/10.1017/s0950268811002068.
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SUMMARYThis study aimed to investigate the relationship between hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) in the ovary and vertical transmission of HBV. HBV DNA and HBV cccDNA were assayed in the ovaries of 33 pregnant women who were positive for HBV DNA. The HBVM (HBV markers, including HBsAg, HBsAb, HBeAg, HBeAb, HBcAb) level and the HBV DNA content in peripheral blood of infants were measured. The overall positive rate of HBV DNA and HBV cccDNA in samples was 51·52% (17/33). The intrauterine infection rate of the infants was 12·12% (4/33). When HBV DNA and HBV cccDNA were both positive, the intrauterine infection rate of infants was significantly higher than when they were both negative (P<0·05). Levels of HBV cccDNA and the rate of positive samples were significantly higher in mothers with infants with intrauterine infection than in those without (P<0·01 andP<0·05, respectively). HBV can infect the human ovary and may transmit to the filial generation via the ovum.
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Ka-Ho Wong, Danny, Man-Fung Yuen, Vincent Wing-Shun Ngai, James Fung und Ching-Lung Lai. „One-Year Entecavir or Lamivudine Therapy Results in Reduction of Hepatitis B Virus Intrahepatic Covalently Closed Circular DNA Levels“. Antiviral Therapy 11, Nr. 7 (01.10.2005): 909–16. http://dx.doi.org/10.1177/135965350601100704.
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Entecavir and lamivudine are potent nucleoside analogues that can suppress hepatitis B virus (HBV) replication. However, the effects of these two antiviral agents on intrahepatic total HBV DNA and covalently closed circular DNA (cccDNA) are not known. In this study, we aimed to assess the effect of 48 weeks of entecavir/lamivudine therapy on intrahepatic total HBV DNA and cccDNA levels. Forty chronic hepatitis B patients, participating in two Phase III entecavir trials at our centre, were randomized to receive 48 weeks of either 0.5 mg once daily of entecavir ( n=21) or 100 mg once daily of lamivudine ( n=19). Their serological, virological and biochemical responses, as well as intrahepatic HBV DNA levels were monitored. There was no significant difference between entecavir and lamivudine therapy in terms of post-treatment serological, virological and biochemical responses. Both nucleoside analogues reduced serum viral load, intrahepatic total HBV DNA, and cccDNA by about 4.8 logs, 2 logs, and 1 log respectively. An increase in the proportion of intrahepatic HBV DNA in the form of cccDNA was seen after 48 weeks of therapy. In conclusion, both entecavir and lamivudine can successfully reduce intrahepatic HBV DNA and cccDNA. CccDNA becomes the dominant form of HBV DNA during viral suppression and is possibly responsible for viral rebound after short-term antiviral therapy.
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Tropberger, Philipp, Alexandre Mercier, Margaret Robinson, Weidong Zhong, Don E. Ganem und Meghan Holdorf. „Mapping of histone modifications in episomal HBV cccDNA uncovers an unusual chromatin organization amenable to epigenetic manipulation“. Proceedings of the National Academy of Sciences 112, Nr. 42 (05.10.2015): E5715—E5724. http://dx.doi.org/10.1073/pnas.1518090112.
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Chronic hepatitis B virus (HBV) infection affects 240 million people worldwide and is a major risk factor for liver failure and hepatocellular carcinoma. Current antiviral therapy inhibits cytoplasmic HBV genomic replication, but is not curative because it does not directly affect nuclear HBV closed circular DNA (cccDNA), the genomic form that templates viral transcription and sustains viral persistence. Novel approaches that directly target cccDNA regulation would therefore be highly desirable. cccDNA is assembled with cellular histone proteins into chromatin, but little is known about the regulation of HBV chromatin by histone posttranslational modifications (PTMs). Here, using a new cccDNA ChIP-Seq approach, we report, to our knowledge, the first genome-wide maps of PTMs in cccDNA-containing chromatin from de novo infected HepG2 cells, primary human hepatocytes, and from HBV-infected liver tissue. We find high levels of PTMs associated with active transcription enriched at specific sites within the HBV genome and, surprisingly, very low levels of PTMs linked to transcriptional repression even at silent HBV promoters. We show that transcription and active PTMs in HBV chromatin are reduced by the activation of an innate immunity pathway, and that this effect can be recapitulated with a small molecule epigenetic modifying agent, opening the possibility that chromatin-based regulation of cccDNA transcription could be a new therapeutic approach to chronic HBV infection.
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Mason, William S., Chunxiao Xu, Huey Chi Low, Jeffry Saputelli, Carol E. Aldrich, Catherine Scougall, Arend Grosse, Richard Colonno, Sam Litwin und Allison R. Jilbert. „The Amount of Hepatocyte Turnover That Occurred during Resolution of Transient Hepadnavirus Infections Was Lower When Virus Replication Was Inhibited with Entecavir“. Journal of Virology 83, Nr. 4 (10.12.2008): 1778–89. http://dx.doi.org/10.1128/jvi.01587-08.
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ABSTRACT Transient hepadnavirus infections can involve spread of virus to the entire hepatocyte population. In this situation hepatocytes present following recovery are derived from infected hepatocytes. During virus clearance antiviral cytokines are thought to block virus replication and formation of new covalently closed circular DNA (cccDNA), the viral transcriptional template. It remains unclear if existing cccDNA is eliminated noncytolytically or if hepatocyte death and proliferation, to compensate for killing of some of the infected hepatocytes, are needed to remove cccDNA from surviving infected hepatocytes. Interpreting the relationship between hepatocyte death and cccDNA elimination requires knowing both the amount of hepatocyte turnover and whether cccDNA synthesis is effectively blocked during the period of immune destruction of infected hepatocytes. We have addressed these questions by asking if treatment of woodchucks with the nucleoside analog inhibitor of viral DNA synthesis entecavir (ETV) reduced hepatocyte turnover during clearance of transient woodchuck hepatitis virus (WHV) infections. To estimate hepatocyte turnover, complexity analysis was carried out on virus-cell DNA junctions created by integration of WHV and present following recovery in the livers of WHV-infected control or ETV-treated woodchucks. We estimated that, on average, 2.2 to 4.8 times less hepatocyte turnover occurred during immune clearance in the ETV-treated woodchucks. Computer modeling of the complexity data suggests that mechanisms in addition to hepatocyte death were responsible for elimination of cccDNA during recovery from transient infections.
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Thermet, Alexandre, Thierry Buronfosse, Bettina Werle-Lapostolle, Michele Chevallier, Pierre Pradat, Christian Trepo, Fabien Zoulim und Lucyna Cova. „DNA vaccination in combination or not with lamivudine treatment breaks humoral immune tolerance and enhances cccDNA clearance in the duck model of chronic hepatitis B virus infection“. Journal of General Virology 89, Nr. 5 (01.05.2008): 1192–201. http://dx.doi.org/10.1099/vir.0.83583-0.
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This study used a duck hepatitis B virus (DHBV) model to evaluate whether a novel DNA vaccination protocol alone or associated with antiviral (lamivudine) treatment was able to clear the intrahepatic covalently closed, circular viral DNA (cccDNA) pool responsible for persistence of infection. DHBV carriers received DNA vaccine (on weeks 6, 10, 13, 14, 28 and 35) targeting the large envelope and/or core proteins alone or combined with lamivudine treatment (on weeks 1–8) or lamivudine monotherapy. After 10 months of follow-up, a dramatic decrease in viraemia and liver DHBV cccDNA (below 0.08 cccDNA copies per cell) was observed in 9/30 ducks (30 %) receiving DNA mono- or combination therapy, compared with 0/12 (0 %) from lamivudine monotherapy or the control groups, suggesting a significant antiviral effect of DNA immunization. However, association with the drug did not significantly improve DHBV DNA vaccine efficacy (33 % cccDNA clearance for the combination vs 27 % for DNA monotherapy), probably due to the low antiviral potency of lamivudine in the duck model. Seroconversion to anti-preS was observed in 6/9 (67 %) ducks showing cccDNA clearance, compared with 1/28 (3.6 %) without clearance, suggesting a significant correlation (P<0.001) between humoral response restoration and cccDNA elimination. Importantly, an early (weeks 10–12) drop in viraemia was observed in seroconverted animals, and virus replication did not rebound following the cessation of immunotherapy, indicating a sustained effect. This study provides the first evidence that therapeutic DNA vaccination is able to enhance hepadnaviral cccDNA clearance, which is tightly associated with a break in humoral immune tolerance. These results also highlight the importance of antiviral drug potency and an effective DNA immunization protocol for the design of therapeutic vaccines against chronic hepatitis B.
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Balagopal, Ashwin, Hyon S. Hwang, Tanner Grudda, Jeffrey Quinn, Richard K. Sterling, Mark S. Sulkowski und Chloe L. Thio. „Single Hepatocyte Hepatitis B Virus Transcriptional Landscape in HIV Coinfection“. Journal of Infectious Diseases 221, Nr. 9 (19.11.2019): 1462–69. http://dx.doi.org/10.1093/infdis/jiz607.
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Abstract Background Hepatitis B virus (HBV) is a leading cause of liver failure and hepatocellular carcinoma. Approximately 10% of people with HIV also have HBV and are at higher risk of liver disease progression than in HBV monoinfection. Antivirals, common to HIV and HBV, suppress HBV DNA levels but do not eradicate virus because the transcriptional template, covalently closed circular DNA (cccDNA), is long lived in infected hepatocytes. Methods Using single-cell laser capture microdissection, we isolated >1100 hepatocytes from 5 HIV/HBV coinfected persons with increasing exposure to HBV antivirals (HB1–HB5; no exposure to >7 years exposure), quantifying cccDNA and pregenomic RNA (pgRNA) in each cell using droplet digital polymerase chain reaction. Results The proportion of infected hepatocytes decreased with antiviral exposure from 96.4% (HB1) to 29.8% (HB5). Upper cccDNA range and median pgRNA decreased from HB1 to HB5 (P < .05 for both). The amount of pgRNA transcribed per cccDNA also decreased from HB1 to HB5 (P < .05). Cells with inactive pgRNA transcription were enriched from 0% (HB1) to 14.3% (HB5) of infected hepatocytes. Conclusions cccDNA transcription is reduced in HIV/HBV coinfected people with longer antiviral duration. Understanding HBV transcriptional regulation may be critical to develop a functional cure.
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Turton, Kristi L., Vanessa Meier-Stephenson, Maulik D. Badmalia, Carla S. Coffin und Trushar R. Patel. „Host Transcription Factors in Hepatitis B Virus RNA Synthesis“. Viruses 12, Nr. 2 (30.01.2020): 160. http://dx.doi.org/10.3390/v12020160.
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The hepatitis B virus (HBV) chronically infects over 250 million people worldwide and is one of the leading causes of liver cancer and hepatocellular carcinoma. HBV persistence is due in part to the highly stable HBV minichromosome or HBV covalently closed circular DNA (cccDNA) that resides in the nucleus. As HBV replication requires the help of host transcription factors to replicate, focusing on host protein–HBV genome interactions may reveal insights into new drug targets against cccDNA. The structural details on such complexes, however, remain poorly defined. In this review, the current literature regarding host transcription factors’ interactions with HBV cccDNA is discussed.
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Zhang, Henrik, und Thomas Tu. „Approaches to quantifying hepatitis B virus covalently closed circular DNA“. Clinical and Molecular Hepatology 28, Nr. 2 (01.04.2022): 135–49. http://dx.doi.org/10.3350/cmh.2021.0283.
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Chronic hepatitis B is a major cause of liver disease worldwide and is currently incurable. Hepatitis B virus (HBV) covalently closed circular (ccc) DNA is a key form of the virus responsible for its persistence and is the transcriptional template for all viral transcripts. The field is focussed on methods to clear HBV cccDNA but this been limited by technical difficulties in its quantification due to: identical sequence to other forms of HBV DNA; low copy number per cell; and high resistance to denaturation by heat, leading to difficulty using polymerase chain reaction or hybridization methods for detection. A number of assays have been developed in order to overcome these hurdles either directly or detecting cccDNA levels indirectly via its transcriptional products. In this review, we summarize the approaches to cccDNA quantification that are currently used, and outline key open questions in the cccDNA biology field which remain to be answered due to the limitations of current methods.
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Kostyushev, D. S., A. P. Zueva, S. A. Brezgin, A. D. Lipatnikov, E. V. Volchkova, V. V. Maleyev und V. P. Chulanov. „THE ROLE OF DNA-METHYLTRANSFERASES IN THE LIFE CYCLE OF HEPATITIS B VIRUS AND PATHOGENESIS OF CHRONIC HEPATITIS B“. Problems of Virology, Russian journal 63, Nr. 1 (20.02.2018): 19–29. http://dx.doi.org/10.18821/0507-4088-2018-63-1-19-29.
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Chronic hepatitis B is caused by a persistent form of hepatitis B virus, covalently closed circular DNA (cccDNA). Stability of cccDNA is associated with intracellular localization of cccDNA and formation of minichromosome, regulated by epigenetic mechanisms. One of the key mechanisms in epigenetics is methylation of DNA on CpG islands. Expression levels of DNA-methyltransferases (DNMTs) in chronic hepatitis B patients were shown to be upregulated. Nevertheless, the role of DNMTs in the life cycle of HBV and their effects on the cell remain elusive. In this review, we discuss latest achievements on the role of DNMTs in chronic hepatitis B and HBV in vitro models.
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Guo, Haitao, Dong Jiang, Tianlun Zhou, Andrea Cuconati, Timothy M. Block und Ju-Tao Guo. „Characterization of the Intracellular Deproteinized Relaxed Circular DNA of Hepatitis B Virus: an Intermediate of Covalently Closed Circular DNA Formation“. Journal of Virology 81, Nr. 22 (05.09.2007): 12472–84. http://dx.doi.org/10.1128/jvi.01123-07.
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ABSTRACT Covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV) is formed by conversion of capsid-associated relaxed circular DNA (rcDNA) via unknown mechanisms and exists in the nucleus of the infected hepatocyte as a minichromosome that serves as the transcription template for viral RNAs. To study the molecular pathway of cccDNA formation and its regulation by viral and cellular factors, we have established a cell line that supports the replication of an envelope protein-deficient HBV genome in a tetracycline-inducible manner. Following induction of HBV replication, the cells accumulate higher levels of cccDNA as well as larger amounts of deproteinized rcDNA (DP-rcDNA) than cells that replicate wild-type HBV genomes. These results indicate that HBV envelope proteins negatively regulate cccDNA formation, and conversion of DP-rcDNA into cccDNA is a rate-limiting step of cccDNA formation in HepG2 cells. Detailed analyses reveal the following: (i) DP-rcDNA exists in both cytoplasm and nucleus; (ii) while nuclear DP-rcDNA is sensitive to DNase I digestion, a small fraction of cytoplasmic DP-rcDNA is DNase I resistant; (iii) both DNase I-sensitive and -resistant cytoplasmic DP-rcDNAs cosediment with capsids and can be immunoprecipitated with HBV core antibody; and (iv) a primer extension assay maps the 5′ end of the minus strand of DP-rcDNA at the authentic end of virion rcDNA. Hence, our results favor a hypothesis that the removal of viral polymerase protein covalently linked to the 5′ end of the minus-strand DNA occurs inside the capsid in the cytoplasm and most possibly via a reaction that cleaves the phosphodiester bond between the tyrosine of the polymerase and the 5′ phosphoryl group of minus-strand DNA.
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Martinez, Maria Guadalupe, Elena Smekalova, Emmanuel Combe, Francine Gregoire, Fabien Zoulim und Barbara Testoni. „Gene Editing Technologies to Target HBV cccDNA“. Viruses 14, Nr. 12 (28.11.2022): 2654. http://dx.doi.org/10.3390/v14122654.
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Hepatitis B virus (HBV) remains a significant cause of mortality and morbidity worldwide, since chronic HBV infection is associated with elevated risk of cirrhosis and hepatocellular carcinoma. Current licensed therapies against HBV efficiently suppress viral replication; however, they do not have significant effects on the intrahepatic covalently closed circular DNA (cccDNA) of the viral minichromosome responsible for viral persistence. Thus, life-long treatment is required to avoid viral rebound. There is a significant need for novel therapies that can reduce, silence or eradicate cccDNA, thus preventing HBV reemergence after treatment withdrawal. In this review, we discuss the latest developments and applications of gene editing and related approaches for directly targeting HBV DNA and, more specifically, cccDNA in infected hepatocytes.
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王, 宁. „The Research Status of Hepatitis B Virus cccDNA“. Immunology Studies 03, Nr. 02 (2015): 13–18. http://dx.doi.org/10.12677/is.2015.32002.
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Cheng, Jun, Min Quan, Min Li, Shun-ai Liu und Qi Wang. „Regulation Mechanism of HBV cccDNA“. Infection International 1, Nr. 2 (01.06.2012): 65–73. http://dx.doi.org/10.1515/ii-2017-0010.
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Abstract Covalently closed circular (ccc) DNA of hepatitis B virus (HBV) existed in the nuclei of HBV infected hepatocytes with a half-life time of 14.3 years in a mathematic model. Viral protein feedback regulation in HBV life cycle to maintain vital viral replication is an important mechanism. Interleukin-6, epithelial growth factor, heme oxygenase-1, histones, and hepatocyte nuclear factors are demonstrated as the key regulators for HBV life cycle. CpG island structure and methylation status are involved in the regulation of HBV DNA replication. Nucleos(t)ide analogues are widely used in the clinical practice for the treatment of chronic hepatitis B patients, although no evidence indicating a direct inhibiton of HBV cccDNA. In the future, along with the study of HBV life cycle, new drugs including RNA interference technique, will pave the way to eliminate the HBV cccDNA from infected hepatocytes resulting final cure of chronic hepatitis B.
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Kostyusheva, Anastasiya, Dmitry Kostyushev, Sergey Brezgin, Elena Volchkova und Vladimir Chulanov. „Clinical Implications of Hepatitis B Virus RNA and Covalently Closed Circular DNA in Monitoring Patients with Chronic Hepatitis B Today with a Gaze into the Future: The Field Is Unprepared for a Sterilizing Cure“. Genes 9, Nr. 10 (05.10.2018): 483. http://dx.doi.org/10.3390/genes9100483.
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. Chronic hepatitis B virus (HBV) infection has long remained a critical global health issue. Covalently closed circular DNA (cccDNA) is a persistent form of the HBV genome that maintains HBV chronicity. Decades of extensive research resulted in the two therapeutic options currently available: nucleot(s)ide analogs and interferon (IFN) therapy. A plethora of reliable markers to monitor HBV patients has been established, including the recently discovered encapsidated pregenomic RNA in serum, which can be used to determine treatment end-points and to predict the susceptibility of patients to IFN. Additionally, HBV RNA splice variants and cccDNA and its epigenetic modifications are associated with the clinical course and risks of hepatocellular carcinoma (HCC) and liver fibrosis. However, new antivirals, including CRISPR/Cas9, APOBEC-mediated degradation of cccDNA, and T-cell therapies aim at completely eliminating HBV, and it is clear that the diagnostic arsenal for defining the long-awaited sterilizing cure is missing. In this review, we discuss the currently available tools for detecting and measuring HBV RNAs and cccDNA, as well as the state-of-the-art in clinical implications of these markers, and debate needs and goals within the context of the sterilizing cure that is soon to come.
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Zhu, Congqing, Caixia Yang, Yongheng Wang, Gan Lin, Yuhui Yang, Xiaoyong Wang, Jun Zhu et al. „CCCCC pentadentate chelates with planar Möbius aromaticity and unique properties“. Science Advances 2, Nr. 8 (August 2016): e1601031. http://dx.doi.org/10.1126/sciadv.1601031.
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The coordinating atoms in polydentate chelates are primarily heteroatoms. We present the first examples of pentadentate chelates with all binding atoms of the chelating agent being carbon atoms, denoted as CCCCC chelates. Having up to five metal-carbon bonds in the equatorial plane has not been previously observed in transition metal chemistry. Density functional theory calculations showed that the planar metallacycle has extended Craig-Möbius aromaticity arising from 12-center–12-electron dπ-pπ π-conjugation. These planar chelates have broad absorption in the ultraviolet-visible–near-infrared region and, thus, notable photothermal performance upon irradiation by an 808-nm laser, indicating that these chelates have potential applications in photothermal therapy. The combination of facile synthesis, high stability, and broad absorption of these complexes could make the polydentate carbon chain a novel building block in coordination chemistry.
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Kim, Kyongmin. „PPIases Par14/Par17 Affect HBV Replication in Multiple Ways“. Viruses 15, Nr. 2 (06.02.2023): 457. http://dx.doi.org/10.3390/v15020457.
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Human parvulin 14 (Par14) and parvulin 17 (Par17) are peptidyl-prolyl cis/trans isomerases that upregulate hepatitis B virus (HBV) replication by binding to the conserved 133Arg-Pro134 (RP) motif of HBc and core particles, and 19RP20-28RP29 motifs of HBx. In the absence of HBx, Par14/Par17 have no effect on HBV replication. Interaction with Par14/Par17 enhances the stability of HBx, core particles, and HBc. Par14/Par17 binds outside and inside core particles and is involved in HBc dimer–dimer interaction to facilitate core particle assembly. Although HBc RP motif is important for HBV replication, R133 residue is solely important for its interaction with Par14/Par17. Interaction of Par14 and Par17 with HBx involves two substrate-binding residues, Glu46/Asp74 (E46/D74) and E71/D99, respectively, and promotes HBx translocation to the nucleus and mitochondria. In the presence of HBx, Par14/Par17 are efficiently recruited to cccDNA and promote transcriptional activation via specific DNA-binding residues Ser19/44 (S19/44). S19 and E46/D74 of Par14, and S44 and E71/D99 of Par17, are also involved in the recruitment of HBc onto cccDNA. Par14/Par17 upregulate HBV replication via various effects that are mediated in part through the HBx–Par14/Par17–cccDNA complex and triple HBc, Par14/Par17, and cccDNA interactions in the nucleus, as well as via core particle-Par14/Par17 interactions in the cytoplasm.
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Chen, Hua-Pin. „Electronically Tunable Quadrature Oscillator Using Grounded Components with Current and Voltage Outputs“. Scientific World Journal 2014 (2014): 1–8. http://dx.doi.org/10.1155/2014/572165.
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The electronically tunable quadrature oscillator using a single multiple-output current controlled current differencing transconductance amplifier (MO-CCCDTA) and grounded passive components is presented. The proposed configuration uses a single MO-CCCDTA, two grounded capacitors and one grounded resistor. Two high-output impedance quadrature current signals and two quadrature voltage signals with 90° phase difference. The oscillation condition and oscillation frequency of the proposed quadrature oscillator are independently controllable. The use of only grounded passive components makes the proposed circuit ideal for integrated circuit implementation.
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Bockmann, Jan-Hendrik, Daniela Stadler, Yuchen Xia, Chunkyu Ko, Jochen M. Wettengel, Julian Schulze zur Wiesch, Maura Dandri und Ulrike Protzer. „Comparative Analysis of the Antiviral Effects Mediated by Type I and III Interferons in Hepatitis B Virus–Infected Hepatocytes“. Journal of Infectious Diseases 220, Nr. 4 (29.03.2019): 567–77. http://dx.doi.org/10.1093/infdis/jiz143.
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Abstract Background Type III interferons (IFNs) (λ1–3) activate similar signaling cascades as type I IFNs (α and β) via different receptors. Since IFN-α and lymphotoxin-β activate cytosine deamination and subsequent purging of nuclear hepatitis B virus (HBV) DNA, we investigated whether IFN-β and -λ may also induce these antiviral effects in differentiated HBV-infected hepatocytes. Methods After determining the biological activity of IFN-α2, -β1, -λ1, and -λ2 in differentiated hepatocytes, their antiviral effects were analyzed in HBV-infected primary human hepatocytes and HepaRG cells. Results Type I and III IFNs reduced nuclear open-circle DNA and covalently closed circular DNA (cccDNA) levels in HBV-infected cells. IFN-β and -λ were at least as efficient as IFN-α. Differential DNA-denaturing polymerase chain reaction and sequencing analysis revealed G-to-A sequence alterations of HBV cccDNA in IFN-α, -β, and -λ–treated liver cells indicating deamination. All IFNs induced apolipoprotein B messenger RNA–editing enzyme–catalytic polypeptide-like (APOBEC) deaminases 3A and 3G within 24 hours of treatment, but IFN-β and -λ induced longer-lasting expression of APOBEC deaminases in comparison to IFN-α. Conclusions IFN-β, IFN-λ1, and IFN-λ2 induce cccDNA deamination and degradation at least as efficiently as IFN-α, indicating that these antiviral cytokines are interesting candidates for the design of new therapeutic strategies aiming at cccDNA reduction and HBV cure.
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Levrero, M., L. Belloni, F. Guerrieri und N. Pediconi. „CS7.3 cccDNA function and HBV replication“. International Journal of Infectious Diseases 15 (Juli 2011): S6. http://dx.doi.org/10.1016/s1201-9712(11)60027-1.
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Sumiyoshi, Yoshihiro, Kaoru Katoh und Yasuki Endo. „Rotational spectra of the CCCCCl radical“. Chemical Physics Letters 414, Nr. 1-3 (Oktober 2005): 82–86. http://dx.doi.org/10.1016/j.cplett.2005.08.054.
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Spangenberg, Hans Christian, Robert Thimme und Hubert E. Blum. „Tracking cccDNA in chronic HBV infection“. Hepatology 39, Nr. 6 (2004): 1736–38. http://dx.doi.org/10.1002/hep.20272.
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