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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 06 August 2013, Vol.110(32), pp.13126-31
    Description: Human CMV (hCMV) establishes lifelong infections in most of us, causing developmental defects in human embryos and life-threatening disease in immunocompromised individuals. During productive infection, the viral 〉230,000-bp dsDNA genome is expressed widely and in a temporal cascade. The hCMV genome does not carry histones when encapsidated but has been proposed to form nucleosomes after release into the host cell nucleus. Here, we present hCMV genome-wide nucleosome occupancy and nascent transcript maps during infection of permissive human primary cells. We show that nucleosomes occupy nuclear viral DNA in a nonrandom and highly predictable fashion. At early times of infection, nucleosomes associate with the hCMV genome largely according to their intrinsic DNA sequence preferences, indicating that initial nucleosome formation is genetically encoded in the virus. However, as infection proceeds to the late phase, nucleosomes redistribute extensively to establish patterns mostly determined by nongenetic factors. We propose that these factors include key regulators of viral gene expression encoded at the hCMV major immediate-early (IE) locus. Indeed, mutant virus genomes deficient for IE1 expression exhibit globally increased nucleosome loads and reduced nucleosome dynamics compared with WT genomes. The temporal nucleosome occupancy differences between IE1-deficient and WT viruses correlate inversely with changes in the pattern of viral nascent and total transcript accumulation. These results provide a framework of spatial and temporal nucleosome organization across the genome of a major human pathogen and suggest that an hCMV major IE protein governs overall viral chromatin structure and function.
    Keywords: Chip-Chip ; Epigenetic Regulation ; Functional Genomics ; Herpesvirus ; Chromatin -- Genetics ; Cytomegalovirus -- Genetics ; Genome, Viral -- Genetics ; Immediate-Early Proteins -- Genetics ; Nucleosomes -- Genetics
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    Language: English
    In: Immunobiology, November 2016, Vol.221(11), pp.1259-1265
    Description: Our previous results indicate that HBD2 and HBD3 are chemotactic for a broad spectrum of leukocytes in a CCR6- and CCR2-dependent manner. In this study we report that pre-stimulation of primary human macrophages or THP-1 cells with HBD2 or HBD3 results in a synergistic, enhanced expression of pro-inflammatory cytokines and chemokines induced by TLR ligand re-stimulation. Experiments using specific inhibitors of the ATP-gated channel receptor P2X7 or its functional ligand ATP, suggest that the enhanced expression of pro-inflammatory cytokines and chemokines seems to be mediated by P2X7R. Furthermore, our data provide evidence that beta-defensins do not directly interact with P2X7R but rather induce the release of intracellular ATP. Interference with ATP release abrogated the synergistic effect mediated by HBD2 and HBD3 pre-stimulation in THP-1 cells. However, extracellular ATP alone seems not to be sufficient to elicit the enhanced synergistic effect on cytokine and chemokine expression observed by pre-stimulation of primary human macrophages or THP-1 cells with HBD2 or HBD3. Collectively, our findings provide new insights into the molecular mechanisms how HBD2 and HBD3 interact with cells of myeloid origin and demonstrate their immuno-modulating functions during innate immune responses.
    Keywords: Beta-Defensins ; P2x7 Receptor ; Pro-Inflammatory Cytokines ; Tlr Agonists ; Biology
    ISSN: 0171-2985
    E-ISSN: 1878-3279
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  • 3
    Language: English
    In: Journal of virology, September 2012, Vol.86(18), pp.9817-27
    Description: In the nuclei of permissive cells, human cytomegalovirus genomes form nucleosomal structures initially resembling heterochromatin but gradually switching to a euchromatin-like state. This switch is characterized by a decrease in histone H3 K9 methylation and a marked increase in H3 tail acetylation and H3 K4 methylation across the viral genome. We used ganciclovir and a mutant virus encoding a reversibly destabilized DNA polymerase to examine the impact of DNA replication on histone modification dynamics at the viral chromatin. The changes in H3 tail acetylation and H3 K9 methylation proceeded in a DNA replication-independent fashion. In contrast, the increase in H3 K4 methylation proved to depend widely on viral DNA synthesis. Consistently, labeling of nascent DNA using "click chemistry" revealed preferential incorporation of methylated H3 K4 into viral (but not cellular) chromatin during or following DNA replication. This study demonstrates largely selective epigenetic tagging of postreplicative human cytomegalovirus chromatin.
    Keywords: Chromatin -- Genetics ; Cytomegalovirus -- Genetics ; Histones -- Metabolism
    ISSN: 0022538X
    E-ISSN: 1098-5514
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  • 4
    Language: English
    In: Journal of virology, January 2014, Vol.88(2), pp.1228-48
    Description: The 72-kDa immediate early 1 (IE1) protein encoded by human cytomegalovirus (hCMV) is a nuclearly localized promiscuous regulator of viral and cellular transcription. IE1 has long been known to associate with host mitotic chromatin, yet the mechanisms underlying this interaction have not been specified. In this study, we identify the cellular chromosome receptor for IE1. We demonstrate that the viral protein targets human nucleosomes by directly binding to core histones in a nucleic acid-independent manner. IE1 exhibits two separable histone-interacting regions with differential binding specificities for H2A-H2B and H3-H4. The H2A-H2B binding region was mapped to an evolutionarily conserved 10-amino-acid motif within the chromatin-tethering domain (CTD) of IE1. Results from experimental approaches combined with molecular modeling indicate that the IE1 CTD adopts a β-hairpin structure, docking with the acidic pocket formed by H2A-H2B on the nucleosome surface. IE1 binds to the acidic pocket in a way similar to that of the latency-associated nuclear antigen (LANA) of the Kaposi's sarcoma-associated herpesvirus. Consequently, the IE1 and LANA CTDs compete for binding to nucleosome cores and chromatin. Our work elucidates in detail how a key viral regulator is anchored to human chromosomes and identifies the nucleosomal acidic pocket as a joint target of proteins from distantly related viruses. Based on the striking similarities between the IE1 and LANA CTDs and the fact that nucleosome targeting by IE1 is dispensable for productive replication even in "clinical" strains of hCMV, we speculate that the two viral proteins may serve analogous functions during latency of their respective viruses.
    Keywords: Chromosomes, Human -- Virology ; Cytomegalovirus -- Metabolism ; Cytomegalovirus Infections -- Virology ; Immediate-Early Proteins -- Metabolism ; Nucleosomes -- Metabolism
    ISSN: 0022538X
    E-ISSN: 1098-5514
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  • 5
    Language: English
    In: Gastroenterology, April 2015, Vol.148(4), pp.S-579-S-579
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/S0016-5085(15)31958-2 Byline: Dominik Bettenworth, Marcus Mucke, Christiane Geyer, Carsten Holtke, Katrin Schwegmann, Christopher Poremba, Michael Schafers, Dirk Domagk, Philipp Lenz
    Keywords: Medicine
    ISSN: 0016-5085
    E-ISSN: 1528-0012
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  • 6
    Language: English
    In: PLoS ONE, 01 January 2017, Vol.12(2), p.e0172532
    Description: BACKGROUND:Worldwide approximately 7,000 rare diseases have been identified. Accordingly, 4 million individuals live with a rare disease in Germany. The mean time to diagnosis is about 6 years and patients receive several incorrect diagnoses during this time. A multiplicity of factors renders...
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 7
    Language: German
    In: DMW - Deutsche Medizinische Wochenschrift, 2016, Vol.141(17), pp.1229-1234
    Description: Angst ist ein komplexes Geschehen und beeinflusst die Symptomatik, den Krankheitsverlauf und die Lebensqualität von Patienten mit fortschreitenden Erkrankungen. Durch den ganzheitlichen Ansatz einer palliativmedizinischen Versorgung werden die physischen, psychischen, sozialen und spirituellen Dimensionen berücksichtigt. Das Screening und eine frühzeitige Anbindung im Krankheitsverlauf zielen auf eine Verringerung der Symptomlast und eine Steigerung der Lebensqualität.
    Keywords: Herz, Hirn und Psyche ; Angst ; Palliativmedizin ; Lebensqualität ; Symptomkontrolle ; Screeninginstrument ; Anxiety ; Palliative care ; Quality of life ; Symptom control ; Screening tool
    ISSN: 0012-0472
    E-ISSN: 1439-4413
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  • 8
    Language: English
    In: Clinical & Experimental Metastasis, 2016, Vol.33(6), pp.551-562
    Description: Advanced stage colorectal cancer (CRC) is still associated with limited prognosis. For preclinical evaluation of novel therapeutic approaches, murine models with orthotopic tumor growth and distant metastases are required. However, these models usually require surgical procedures possibly influencing tumor immunogenicity and development. The aim of this study was to establish a minimal-invasive endoscopy-based murine orthotopic model of metastatic CRC. During colonoscopy of CD-1 nude and non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice, implantation of Caco-2 and HT-29 CRC cells was performed subcutaneously (s.c.) or orthotopic into the colonic submucosa. White light endoscopy (WLE) and fluorescence endoscopy (FE) were applied for tumor detection in vivo. Ex vivo, resected tumors were examined by fluorescence reflectance imaging (FRI), histology, gelatin zymography and immunohistochemistry. In CD-1 nude mice, marked tumor growth was observed within 14 days after subcutaneous implantation while submucosal implantation failed to induce CRC after 17 weeks. In contrast, in NOD/SCID mice submucosal injection of HT-29 cells resulted in pronounced tumor growth 12 days post injectionem . Subsequently, rapid tumor expansion occurred, occupying the entire colonic circumference. Importantly, post mortem histological analyses confirmed liver metastases in 28.6 % and peritoneal metastases in 14.3 % of all mice. FRI and gelatin zymography did not detect a significantly increased matrix metalloproteinases (MMPs) expression in s.c. implanted tumors while MMP-tracer uptake was significantly enhanced in orthotopic implanted tumors. Neither s.c. nor orthotopic Caco-2 cell implantation resulted in tumor development. We successfully established an endoscopy-based model of metastatic CRC in immunodeficient mice.
    Keywords: Colorectal cancer ; Metastasis ; Matrix metalloproteinase ; Fluorescence reflectance imaging ; Fluorescence endoscopy ; Endoscopy
    ISSN: 0262-0898
    E-ISSN: 1573-7276
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  • 9
    Language: English
    In: Journal of Cranio-Maxillo-Facial Surgery, March 2015, Vol.43(2), pp.204-207
    Description: Microvascular sutured anastomosis remains the gold standard in microvascular flap surgery but is technically challenging, time-consuming, and sometimes unreliable. The goal of our study has been to develop a microvascular stenting system that can be used for microvascular anastomosis, even without the use of a microscope. Custom-made stainless-steel stents were used to re-establish vessel continuity after the severance of the abdominal aortic vessel in nine rats. At 30 min after re-opening the blood flow, Doppler flowmetry and indocyanine green (ICG) angiography were used to assess vessel patency, and vessels were inspected microscopically for signs of thrombosis. Eight of the nine animals survived the procedure. In one case, the abdominal aorta was torn during balloon dilation of the stent. Four out of the nine stent anastomoses showed an excellent fit. In the remaining four cases, a collagen membrane and fibrin glue were successfully used to stop vascular leakage. However, these additional steps might have had a negative impact on vessel patency, and thrombus formation impaired blood flow completely in one case. Microvascular stent anastomosis is feasible and might in some cases be superior to standard sutured anastomosis. However, a number of technical difficulties remain to be addressed, and long-term results are not yet available.
    Keywords: Microsurgery ; Stents ; Minimally Invasive ; Anastomosis ; Dentistry
    ISSN: 1010-5182
    E-ISSN: 1878-4119
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  • 10
    Language: English
    In: Inflammatory bowel diseases, 19 December 2017, Vol.24(1), pp.111-122
    Description: To facilitate onsite decision-making during endoscopy, both accurate detection and in vivo characterization of preneoplasia are prerequisites. However, no endoscopy technique is available that meets both demands satisfactorily. We evaluated endothelin-receptor A (ETAR)-guided fluorescence endoscopy (FE) in vivo and fluorescence reflectance imaging (FRI) ex vivo for detection and characterization of early dysplastic colitis-associated colonic lesions. Colorectal cancerogenesis was investigated in the inflammatory driven AOM-DSS model and spontaneous adenoma development in ApcMin mice. A Cy5.5-labeled nonpeptidic ETAR-specific imaging probe was injected intravenously to assess tumor development in vivo by white light endoscopy (WLE) and FE. Ex vivo tumors were evaluated by FRI, histological examination, and western blot analysis. In addition, tissue samples from patients with colitis-associated malignant and nonmalignant mucosal alterations were analyzed. Specificity experiments were performed using an unspecific Cy3.5-glycine tracer. Overall, 62 adenomas were observed. FE was able to detect and quantify ETAR expression targeting the ETAR-specific photoprobe. A significantly higher fluorescent contrast was detected in colonic adenomas compared to adjacent nonmalignant mucosa by FE (64.3 ± 7.9 vs. 56.6. ± 7.0; P 〈 0.001). These results were confirmed by FRI examination, immunochemistry, and western blot analysis. Additionally, ETAR expression in samples from human patients with colitis-associated cancer was highly elevated compared to nonmalignant alterations. Specificity experiments indicated a high binding-specificity of the applied ETAR photoprobe (1.4 ± 0.3 vs. 2.5 ± 0.7; P 〈 0.001). We introduced ETAR guided FE in mice for successful in vivo detection and characterization of colorectal neoplasia on a molecular level.
    Keywords: Colitis Associated Cancer ; Colorectal Cancer ; Fluorescence Imaging ; Ulcerative Colitis ; Adenoma -- Diagnosis ; Colitis -- Complications ; Colonic Neoplasms -- Diagnosis ; Colonoscopy -- Methods ; Intestinal Mucosa -- Metabolism ; Optical Imaging -- Methods ; Receptor, Endothelin A -- Metabolism
    ISSN: 10780998
    E-ISSN: 1536-4844
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