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- 검색키워드
- 저자 : Windisch, Marc P (검색결과 11 건)
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Ko, Chunkyu,Lee, Sooyoung,Windisch, Marc P.,Ryu, Wang-Shick American Society for Microbiology 2014 Journal of virology Vol.88 No.23
<P>DDX3 is a member of the DEAD-box RNA helicase family, involved in mRNA metabolism, including transcription, splicing, and translation. We previously identified DDX3 as a hepatitis B virus (HBV) polymerase (Pol) binding protein, and by using a transient transfection, we found that DDX3 inhibits HBV replication at the posttranscriptional level, perhaps following encapsidation. To determine the exact mechanism of the inhibition, we here employed a diverse HBV experimental system. Inconsistently, we found that DDX3-mediated inhibition occurs at the level of transcription. By using tetracycline-inducible HBV-producing cells, we observed that lentivirus-mediated DDX3 expression led to a reduced level of HBV RNAs. Importantly, knockdown of DDX3 by short hairpin RNA resulted in augmentation of HBV RNAs in two distinct HBV replication systems: (i) tetracycline-inducible HBV-producing cells and (ii) constitutive HBV-producing HepG2.2.15 cells. Moreover, DDX3 knockdown in HBV-susceptible HepG2-NTCP cells, where covalently closed circular DNA (cccDNA) serves as the template for viral transcription, resulted in increased HBV RNAs, validating that transcription regulation by DDX3 occurs on a physiological template. Overall, our results demonstrate that DDX3 represents an intrinsic host antiviral factor that restricts HBV transcription.</P><P><B>IMPORTANCE</B> Upon entry into host cells, viruses encounter host factors that restrict viral infection. During evolution, viruses have acquired the ability to subvert cellular factors that adversely affect their replication. Such host factors include TRIM5α and APOBEC3G, which were discovered in retroviruses. The discovery of host restriction factors provided deeper insight into the innate immune response and viral pathogenesis, leading to better understanding of host-virus interactions. In contrast to the case with retroviruses, little is known about host factors that restrict hepatitis B virus (HBV), a virus distantly related to retroviruses. DDX3 DEAD box RNA helicase is best characterized as an RNA helicase involved in RNA metabolism, such as RNA processing and translation. Here, we show that DDX3 inhibits HBV infection at the level of viral transcription.</P>
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Automated genome-wide visual profiling of cellular proteins involved in HIV infection.
Genovesio, Auguste,Kwon, Yong-Jun,Windisch, Marc P,Kim, Nam Youl,Choi, Seo Yeon,Kim, Hi Chul,Jung, Sungyong,Mammano, Fabrizio,Perrin, Virginie,Boese, Annette S,Casartelli, Nicoletta,Schwartz, Olivier Mary Ann Liebert, Inc 2011 Journal of biomolecular screening Vol.16 No.9
<P>Recent genome-wide RNAi screens have identified >842 human genes that affect the human immunodeficiency virus (HIV) cycle. The list of genes implicated in infection differs between screens, and there is minimal overlap. A reason for this variance is the interdependence of HIV infection and host cell function, producing a multitude of indirect or pleiotropic cellular effects affecting the viral infection during RNAi screening. To overcome this, the authors devised a 15-dimensional phenotypic profile to define the viral infection block induced by CD4 silencing in HeLa cells. They demonstrate that this phenotypic profile excludes nonspecific, RNAi-based side effects and viral replication defects mediated by silencing of housekeeping genes. To achieve statistical robustness, the authors used automatically annotated RNAi arrays for seven independent genome-wide RNAi screens. This identified 56 host genes, which reliably reproduced CD4-like phenotypes upon HIV infection. The factors include 11 known HIV interactors and 45 factors previously not associated with HIV infection. As proof of concept, the authors confirmed that silencing of PAK1, Ku70, and RNAseH2A impaired HIV replication in Jurkat cells. In summary, multidimensional, visual profiling can identify genes required for HIV infection.</P>
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Sex Differences in Serum C-Reactive Protein Course after Total Hip Arthroplasty
Sebastian Rohe,Eric Röhner,Christoph Windisch,Georg Matziolis,Steffen Brodt,Sabrina Böhle 대한정형외과학회 2022 Clinics in Orthopedic Surgery Vol.14 No.1
Background: Gender-specific medicine has become an important part in investigating the course of various diseases. C-reactive protein (CRP) is used as an inflammatory marker for detecting inflammations and even infections after total hip arthroplasty (THA). The general course of CRP after THA is well known, but there is controversy about its association with sex. Therefore, we aimed to investigate if there is an influence of sex on the CRP after THA in the first 10 days after operation in a complication-free course in male and female patients and to re-evaluate the specific postoperative CRP course with its maximum on the second to third postoperative days. Methods: We retrospectively reviewed patients who had been treated with THA due to primary osteoarthritis through the same approach using an equal model of a cementless stem and a cup and complication-free between 2013 and 2016. Patients with active inflammation, rheumatoid arthritis, secondary arthrosis, active cancer disease, and documented postoperative complications were not included. The CRP values before THA and up to 10 days after THA were recorded and tested for sex discrepancy. Factor analyses were performed, and CRP values were adjusted for confounders (age, operation time, diabetes mellitus, and body mass index [BMI]). Results: A total of 1,255 patients (728 women and 527 men) were finally analyzed. Men were younger and had a longer operation time and a higher BMI compared to women. The prevalence of overweight was higher in men, while obesity (BMI > 40 kg/m²), diabetes mellitus, renal failure, and American Society of Anaesthesiologists status showed no significant difference between men and women. Men had significantly higher CRP values than women between the 2nd and the 7th postoperative days, with the largest difference on the 4th postoperative day (men, 130.48 mg/L; women, 87.26 mg/L; p = 0.018). Conclusions: Based on the results of more precise sex-specific evaluation of the postoperative CRP course after THA, the present study showed for the first time that there was a gender discrepancy in the CRP course after complication-free THA in the first 7 postoperative days. Furthermore, this study confirmed the postoperative CRP course with its maximum on the third postoperative day.
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Siddharta, Anindya,Pfaender, Stephanie,Vielle, Nathalie Jane,Dijkman, Ronald,Friesland, Martina,Becker, Britta,Yang, Jaewon,Engelmann, Michael,Todt, Daniel,Windisch, Marc P.,Brill, Florian H.,Steinman Oxford University Press 2017 The Journal of Infectious Diseases Vol.215 No.6
<P><B>Abstract</B></P><P>The World Health Organization (WHO) published 2 alcohol-based formulations to be used in healthcare settings and for outbreak-associated infections, but inactivation efficacies of these products have not been determined against (re-)emerging viruses. In this study, we evaluated the virucidal activity of these WHO products in a comparative analysis. Zika virus (ZIKV), Ebola virus (EBOV), severe acute respiratory syndrome coronavirus (SARS-CoV), and Middle East respiratory syndrome coronavirus (MERS-CoV) as (re-)emerging viral pathogens and other enveloped viruses could be efficiently inactivated by both WHO formulations, implicating their use in healthcare systems and viral outbreak situations.</P>
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Lee, M.,Yang, J.,Park, S.,Jo, E.,Kim, H.Y.,Bae, Y.S.,Windisch, M.P. Elsevier/North-Holland 2016 ANTIVIRAL RESEARCH Vol.132 No.-
<P>Hepatitis C virus (HCV) is considered a major public health concern worldwide. Despite recent advances in curing chronic hepatitis C, unmet medical needs still remain, especially due to the high economic burden of therapies. Accordingly, our study aimed to identify affordable novel HCV inhibitors by screening of natural product compound libraries. We identified micrococcin P1, a macrocyclic peptide antibiotic, inhibiting HCV entry in a pan-genotypic manner with an EC50 range of 0.1-0.5 mu M. Micrococcin P1 interfered with HCV entry at an attachment step. Furthermore, micrococcin P1 efficiently inhibited HCV spread by blocking cell-free infection as well as cell-to-cell transmission, without affecting the secretion of infectious virions. Interestingly, the putative molecular target of micrococcin P1 is glycoprotein E2 (IIe-630-Thr), as revealed by selection for viral drug resistance. In addition, micrococcin P1 inhibited sofosbuvir-resistant HCV strains and showed synergy in combination with selected HCV drugs, suggesting an alternative treatment paradigm for patients. In conclusion, we identified micrococcin P1 as specifically inhibiting entry of all HCV genotypes and demonstrated that micrococcin P1 potentially could add value to therapies in combination with current HCV interventions. (C) 2016 Elsevier B.V. All rights reserved.</P>
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Park, D.S.,Jo, E.,Choi, J.,Lee, M.,Kim, S.,Kim, H.Y.,Nam, J.,Ahn, S.,Hwang, J.Y.,Windisch, M.P. S.E.C.T. [etc.] ; Elsevier Science Ltd 2017 European journal of medicinal chemistry Vol.140 No.-
Upon high-throughput screening of synthetic small molecule libraries with the infectious hepatitis C virus (HCV) cell culture system, we identified an iminodipyridinopyrimidine (IDPP) scaffold. IDPP did not inhibit HCV replication, but exhibited very potent inhibitory activity on early and late steps of HCV life cycle. Applying an intensive structure-activity relationship (SAR) study, a promising IDPP Lead compound (12c) with excellent potency (EC<SUB>50</SUB> = 10 nM), high safety margin (SI > 2000), and an acceptable stability in human and rat liver microsomes (t<SUB>½</SUB> >60 min) was identified. Overall, our results suggest that the IDPP scaffold could be used for the development of novel HCV interventions.
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Kim, Hee-Young,Kong, Sunju,Oh, Sangmi,Yang, Jaewon,Jo, Eunji,Ko, Yoonae,Kim, Soo-Hyun,Hwang, Jong Yeon,Song, Rita,Windisch, Marc P. Elsevier 2016 ANTIVIRAL RESEARCH Vol.129 No.-
<P>Upon screening synthetic small molecule libraries with the infectious hepatitis C virus (HCV) cell culture system, we identified a benzothiazepinecarboxamide (BTC) scaffold that inhibits HCV. A structure-activity relationship (SAR) study with BTC5 was performed, and modifications that led to nanomolar antiviral activity and improved the selective index (CC50/EC50) by more than 1000-fold were identified. In addition, a pharmacophore modeling study determined that the tricyclic core and positive charge on the piperidine moiety were essential for antiviral activity. Furthermore, we demonstrated that BTC interferes with HCV glycoprotein E1/E2-mediated viral entry and the generation of infectious virions by using HCV pseudoparticle and cell culture supernatant transfer assays, respectively. BTC showed potent antiviral activity against HCV genotype 2 (EC50 = 0.01 +/- 0.01 mu M), but was less potent against a genotype 1/2 chimeric virus (EC50 = 2.71 +/- 0.05 mu M), which expressed the structural proteins of HCV genotype 1. In summary, we identified, optimized, and characterized novel BTC inhibitors that interfere with early and late steps of the HCV viral life cycle. (C) 2016 Elsevier B.V. All rights reserved.</P>
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Kim, H.Y.,Li, X.,Jones, C.T.,Rice, C.M.,Garcia, J.M.,Genovesio, A.,Hansen, M.A.E.,Windisch, M.P. Elsevier/North-Holland 2013 Antiviral research Vol.99 No.1
Hepatitis C virus (HCV) infection is a global health concern with chronic liver damage threatening 3% of the world's population. To date, the standard of care is a combination of pegylated interferon-alpha with ribavirin, and recently two direct acting antivirals have entered the clinics. However, because of side effects, drug resistance and viral genotype-specific differences in efficacy current and potentially also future therapies have their limitations. Here, we describe the development of a phenotypic high-throughput assay to identify new cross-genotype inhibitors with novel mechanism of action, by combining a genotype (gt) 1 replicon with the infectious HCV gt2 cell culture system. To develop this phenotypic multiplex assay, HCV reporter cells expressing RFP-NLS-IPS and gt1b replicon cells expressing NS5A-GFP were co-plated and treated with compounds followed by inoculation with gt2a HCV. At 72h post treatment, RFP translocation as a marker for HCV infection and GFP fluorescence intensity as a marker for gt1 RNA replication were measured. Additionally, the total cell number, which serves as an indicator of cytotoxicity, was determined. This phenotypic strategy supports multi-parameter data acquisition from a single well to access cross-genotypic activity, provides an indication of the stage of the viral life cycle targeted, and also assesses compound cytotoxicity. Taken together, this multiplex phenotypic platform facilitates the identification of novel compounds for drug development and chemical probes for continuing efforts to understand the HCV life cycle.
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