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Search Results: 1 - 10 of 681 matches for " Michaela Scherr "
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RNA-Mediated Gene Silencing in Hematopoietic Cells
Letizia Venturini,Matthias Eder,Michaela Scherr
Journal of Biomedicine and Biotechnology , 2006, DOI: 10.1155/jbb/2006/87340
Abstract: In the past few years, the discovery of RNA-mediated gene silencing mechanisms, like RNA interference (RNAi), has revolutionized our understanding of eukaryotic gene expression. These mechanisms are activated by double-stranded RNA (dsRNA) and mediate gene silencing either by inducing the sequence-specific degradation of complementary mRNA or by inhibiting mRNA translation. RNAi now provides a powerful experimental tool to elucidate gene function in vitro and in vivo, thereby opening new exciting perspectives in the fields of molecular analysis and eventually therapy of several diseases such as infections and cancer. In hematology, numerous studies have described the successful application of RNAi to better define the role of oncogenic fusion proteins in leukemogenesis and to explore therapeutic approaches in hematological malignancies. In this review, we highlight recent advances and caveats relating to the application of this powerful new methodology to hematopoiesis.
CD7 in acute myeloid leukemia: correlation with loss of wild-type CEBPA, consequence of epigenetic regulation
Sonja R?hrs, Michaela Scherr, Julia Romani, Margarete Zaborski, Hans G Drexler, Hilmar Quentmeier
Journal of Hematology & Oncology , 2010, DOI: 10.1186/1756-8722-3-15
Abstract: As already described for primary AML cells, the majority of AML cell lines tested were either C/EBPα+/CD7- or C/EBPα-/CD7+. However, the existence of isolated CD7+ cell lines expressing wild-type C/EBPα challenges the notion that C/EBPα acts as a unique repressor of CD7. Furthermore, ectopic expression of CEBPA did not reduce CD7 in CD7+ cells and knock-down of C/EBPα failed to induce CD7 in CD7- cells. In contrast, the DNA demethylating agent Aza-2'deoxycytidine triggered CD7 expression in CD7- AML and in T-cell lines suggesting epigenetic regulation of CD7. Bisulfite sequencing data confirmed that CpGs in the CD7 exon1 region are methylated in CD7- cell lines, and unmethylated in CD7+ cell lines.We confirmed an inverse correlation between the expression of wild-type CEBPA and of CD7 in AML cells. Our results contradict the hypothesis that C/EBPα acts as repressor for CD7, and instead show that epigenetic mechanisms are responsible for CD7 regulation, in AML cells as well as in T-cells, the typical CD7 expressing cell type.CCAAT/enhancer binding factor alpha (CEBPA), located on chromosome 19q13.1 encodes a transcription factor that is of importance for granulocytic differentiation [1]. C/EBPα is upregulated during myelomonocytic development and positively affects expression of granulocyte differentiation related genes such as the G-CSF receptor (GCSFR), myeloperoxidase and neutrophil elastase (ELA2) [2-4]. CEBPA mutations are found in 5 - 14% of acute myeloid leukemia (AML) cases [5]. C/EBPα mutant proteins block the effect of wild-type C/EBPα on target genes in a dominant-negative manner [6]. This might be the reason why patients with CEBPA mutations and those with a silenced CEBPA promoter are found in the same AML subclass according to gene expression profiling [7]. Also expression of the T-cell marker CD7 has been associated with CEBPA mutations and with CEBPA hypermethylation [7,8].CD7 is expressed in 30% of AML cases and CD7 positivity is linked with poor pro
Higher Education for Complex Real-World Problems and Innovation: A Tribute to Heufler’s Industrial Design Approach  [PDF]
Gerald Steiner, Johannes Scherr
Creative Education (CE) , 2013, DOI: 10.4236/ce.2013.47A2016
Abstract: This article appraises an internationally top ranked higher education program in industrial design, whose stated mission is to enhance students’ ability to deal with complex real-world problems and thereby develop (sustainable) innovation. At the outset, we discuss in general terms—in our view—the indispensable essentials of a higher education program that specifically aims to equip students with the competences needed to successfully deal with such complex real-world problems. In the second part, we specifically examine Heufler’s SchoolofIndustrial DesigninGraz(Austria), its development and characteristics. A summary of general implications for higher education and lessons learnt from this top industrial design program concludes the article. Our analysis suggests that the school’s success is based on a few key cornerstones: 1) The program has a clear mission, which has been communicated early on, internally and externally; 2) Strong leadership, which enables continuity and high-quality output (e.g., attracts high-quality input reflected in the profile of applicants to the program); 3) Real-world projects with co-leadership from industry; 4) Provision of a supportive learning environment which extends beyond lecture times and which is conducive for collaborative creativity; and 5) Faculty are professional experts who focus on problemand project based learning approaches which aim at the joint development of personal, professional domain, systemic, creativity, and sociocultural (collaborative) competence of the students. The authors of this article have been involved with Heufler’sSchoolofIndustrial Designsince its establishment in 1995; they speak on behalf of Gerhard Heufler, the founder and head of this program, who unexpectedly passed away in April 2013. His remarkable leadership has enabled an extraordinary program in higher education with the explicit aim to provide students with competences needed to successfully deal with complex real-world problems.
Polycomb repressor complex 2 regulates HOXA9 and HOXA10, activating ID2 in NK/T-cell lines
Stefan Nagel, Letizia Venturini, Victor E Marquez, Corinna Meyer, Maren Kaufmann, Michaela Scherr, Roderick AF MacLeod, Hans G Drexler
Molecular Cancer , 2010, DOI: 10.1186/1476-4598-9-151
Abstract: This analysis showed high expression levels of HOXA9, HOXA10 and ID2 in NK-cell lines in addition to T-cell line LOUCY, suggesting leukemic deregulation therein. Overexpression experiments, chromatin immuno-precipitation and promoter analysis demonstrated that HOXA9 and HOXA10 directly activated expression of ID2. Concomitantly elevated expression levels of HOXA9 and HOXA10 together with ID2 in cell lines containing MLL translocations confirmed this form of regulation in both ALL and acute myeloid leukemia. Overexpression of HOXA9, HOXA10 or ID2 resulted in repressed expression of apoptosis factor BIM. Furthermore, profiling data of genes coding for chromatin regulators of homeobox genes, including components of polycomb repressor complex 2 (PRC2), indicated lacking expression of EZH2 in LOUCY and exclusive expression of HOP in NK-cell lines. Subsequent treatment of T-cell lines JURKAT and LOUCY with DZNep, an inhibitor of EZH2/PRC2, resulted in elevated and unchanged HOXA9/10 expression levels, respectively. Moreover, siRNA-mediated knockdown of EZH2 in JURKAT enhanced HOXA10 expression, confirming HOXA10-repression by EZH2. Additionally, profiling data and overexpression analysis indicated that reduced expression of E2F cofactor TFDP1 contributed to the lack of EZH2 in LOUCY. Forced expression of HOP in JURKAT cells resulted in reduced HOXA10 and ID2 expression levels, suggesting enhancement of PRC2 repression.Our results show that major differentiation factors of the NK-cell lineage, including HOXA9, HOXA10 and ID2, were (de)regulated via PRC2 which therefore contributes to T-cell leukemogenesis.Adult lymphopoiesis starts with progenitor cells which originate from CD34+ hematopoietic stem cells (HSC) in the bone marrow. While the development of natural killer (NK)- cells completes primarily in the bone marrow, T-cells finalize their differentiation in the thymus [1-3]. Nevertheless, the facts that NK-cell differentiation also occurs in the thymus and early thymoc
überlebter pl tzlicher Herzkreislaufstillstand bei einem Patienten ohne strukturelle Herzerkrankung: das Brugada-Syndrom
Scherr D
Journal für Kardiologie , 2003,
Abstract: Bei überlebtem pl tzlichem Herzkreislaufstillstand bzw. bei Patienten mit Synkopen unklarer Genese ist das Brugada-Syndrom eine m gliche Differentialdiagnose. Bei Verdacht auf Brugada-Syndrom und unauff lligem 12-Kanal-EKG sollte ein Ajmalin-Test durchgeführt werden. Bei Patienten mit Brugada-Syndrom ist eine ICD-Implantation indiziert. Weiters sollte ein Familien-Screening durchgeführt werden.
NK-like homeodomain proteins activate NOTCH3-signaling in leukemic T-cells
Stefan Nagel, Letizia Venturini, Grzegorz K Przybylski, Piotr Grabarczyk, Corinna Meyer, Maren Kaufmann, Karin Battmer, Christian A Schmidt, Hans G Drexler, Michaela Scherr, Roderick AF MacLeod
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-371
Abstract: Specific gene activity was examined by quantitative real-time PCR, and globally by expression profiling. Proteins were analyzed by western blot, immuno-cytology and immuno-precipitation. For overexpression studies cell lines were transduced by lentiviruses.Quantification of MSX2 mRNA in primary hematopoietic cells demonstrated higher levels in CD34+ stem cells as compared to peripheral blood cells and mature CD3+ T-cells. Furthermore, analysis of MSX2 expression levels in T-cell lines after treatment with core thymic factors confirmed their involvement in regulation. These results indicated that MSX2 represents an hematopoietic NKL family member which is downregulated during T-cell development and may functionally substituted by oncogenic NKLs. For functional analysis JURKAT cells were lentivirally transduced, overexpressing either MSX2 or oncogenic TLX1 and NKX2-5, respectively. These cells displayed transcriptional activation of NOTCH3-signaling, including NOTCH3 and HEY1 as analyzed by gene expression profiling and quantitative RT-PCR, and consistently attenuated sensitivity to gamma-secretase inhibitor as analyzed by MTT-assays. Furthermore, in addition to MSX2, both TLX1 and NKX2-5 proteins interacted with NOTCH-pathway repressors, SPEN/MINT/SHARP and TLE1/GRG1, representing a potential mechanism for (de)regulation. Finally, elevated expression of NOTCH3 and HEY1 was detected in primary TLX1/3 positive T-ALL cells corresponding to the cell line data.Identification and analysis of MSX2 in hematopoietic cells implicates a modulatory role via NOTCH3-signaling in early T-cell differentiation. Our data suggest that reduction of NOTCH3-signaling by physiological downregulation of MSX2 expression during T-cell development is abrogated by ectopic expression of oncogenic NKLs, substituting MSX2 function.T-cells derive from early progenitor cells which in turn originate from CD34+ hematopoietic stem cells (HSC). After emigrating from the bone marrow, T-cells complete dev
Hypomethylation and expression of BEX2, IGSF4 and TIMP3 indicative of MLL translocations in Acute Myeloid Leukemia
Sonja R?hrs, Wilhelm G Dirks, Claus Meyer, Rolf Marschalek, Michaela Scherr, Robert Slany, Andrew Wallace, Hans G Drexler, Hilmar Quentmeier
Molecular Cancer , 2009, DOI: 10.1186/1476-4598-8-86
Abstract: Using MS-MLPA (methylation-specific multiplex ligation-dependent probe amplification assay), methylation of 24 different TSG was analyzed in 28 MLLmu and MLLwt acute leukemia cell lines. On average, 1.8/24 TSG were methylated in MLLmu AML cells, while 6.2/24 TSG were methylated in MLLwt AML cells. Hypomethylation and expression of the TSG BEX2, IGSF4 and TIMP3 turned out to be characteristic of MLLmu AML cell lines. MLLwt AML cell lines displayed hypermethylated TSG promoters resulting in transcriptional silencing. Demethylating agents and inhibitors of histone deacetylases restored expression of BEX2, IGSF4 and TIMP3, confirming epigenetic silencing of these genes in MLLwt cells. The positive correlation between MLL translocation, TSG hypomethylation and expression suggested that MLL fusion proteins were responsible for dysregulation of TSG expression in MLLmu cells. This concept was supported by our observation that Bex2 mRNA levels in MLL-ENL transgenic mouse cell lines required expression of the MLL fusion gene.These results suggest that the conspicuous expression of the TSG BEX2, IGSF4 and TIMP3 in MLLmu AML cell lines is the consequence of altered epigenetic properties of MLL fusion proteins.Translocations of the Mixed Lineage Leukemia (MLL) gene occur in a subset of acute leukemias. The correlation between MLL translocations and expression of specific gene clusters is so evident that "mixed lineage leukemia", originally applied to biphenotypic acute leukemia cells, is now used to describe the MLL mutant (MLLmu) acute leukemias [1]. High expression levels of a set of HOXA cluster genes are characteristic of MLL mutations in primary acute lymphoblastic leukemia (ALL) cells, and in MLLmu ALL cell lines [1,2]. For acute myeloid leukemia (AML) cell lines, a similar correlation exists between MLL translocations and expression of the gene brain expressed X-linked 2 (BEX2, formerly called BEX1) [3]. In healthy people, BEX2 is expressed in the brain and, more weakly,
MicroRNA-20a Constrains p300-Driven Myocardial Angiogenic Transcription by Direct Targeting of p300
Lina A. Shehadeh, Salil Sharma, M?nica Pessanha, Jian Qin Wei, Jing Liu, Huijun Yuan, Claudia O. Rodrigues, Michaela Scherr, Nicholas F. Tsinoremas, Nanette H. Bishopric
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0079133
Abstract: Objective To characterize downstream effectors of p300 acetyltransferase in the myocardium. Background Acetyltransferase p300 is a central driver of the hypertrophic response to increased workload, but its biological targets and downstream effectors are incompletely known. Methods and Results Mice expressing a myocyte-restricted transgene encoding acetyltransferase p300, previously shown to develop spontaneous hypertrophy, were observed to undergo robust compensatory blood vessel growth together with increased angiogenic gene expression. Chromatin immunoprecipitation demonstrated binding of p300 to the enhancers of the angiogenic regulators Angpt1 and Egln3. Interestingly, p300 overexpression in vivo was also associated with relative upregulation of several members of the anti-angiogenic miR-17~92 cluster in vivo. Confirming this finding, both miR-17-3p and miR-20a were upregulated in neonatal rat ventricular myocytes following adenoviral transduction of p300. Relative expression of most members of the 17~92 cluster was similar in all 4 cardiac chambers and in other organs, however, significant downregulation of miR-17-3p and miR-20a occurred between 1 and 8 months of age in both wt and tg mice. The decline in expression of these microRNAs was associated with increased expression of VEGFA, a validated miR-20a target. In addition, miR-20a was demonstrated to directly repress p300 expression through a consensus binding site in the p300 3′UTR. In vivo transduction of p300 resulted in repression both of p300 and of p300-induced angiogenic transcripts. Conclusion p300 drives an angiogenic transcription program during hypertrophy that is fine-tuned in part through direct repression of p300 by miR-20a.
BCR-ABL Affects STAT5A and STAT5B Differentially
Michael Schaller-Sch?nitz, David Barzan, Andrew J. K. Williamson, John R. Griffiths, Iris Dallmann, Karin Battmer, Arnold Ganser, Anthony D. Whetton, Michaela Scherr, Matthias Eder
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0097243
Abstract: Signal transducers and activators of transcription (STATs) are latent cytoplasmic transcription factors linking extracellular signals to target gene transcription. Hematopoietic cells express two highly conserved STAT5-isoforms (STAT5A/STAT5B), and STAT5 is directly activated by JAK2 downstream of several cytokine receptors and the oncogenic BCR-ABL tyrosine kinase. Using an IL-3-dependent cell line with inducible BCR-ABL-expression we compared STAT5-activation by IL-3 and BCR-ABL in a STAT5-isoform specific manner. RNAi targeting of STAT5B strongly inhibits BCR-ABL-dependent cell proliferation, and STAT5B but not STAT5A is essential for BCL-XL-expression in the presence of BCR-ABL. Although BCR-ABL induces STAT5-tyrosine phosphorylation independent of JAK2-kinase activity, BCR-ABL is less efficient in inducing active STAT5A:STAT5B-heterodimerization than IL-3, leaving constitutive STAT5A and STAT5B-homodimerization unaffected. In comparison to IL-3, nuclear accumulation of a STAT5A-eGFP fusion protein is reduced by BCR-ABL, and BCR-ABL tyrosine kinase activity induces STAT5A-eGFP translocation to the cell membrane and co-localization with the IL-3 receptor. Furthermore, BCR-ABL-dependent phosphorylation of Y682 in STAT5A was detected by mass-spectrometry. Finally, RNAi targeting STAT5B but not STAT5A sensitizes human BCR-ABL-positive cell lines to imatinib-treatment. These data demonstrate differences between IL-3 and BCR-ABL-mediated STAT5-activation and isoform-specific effects, indicating therapeutic options for isoform-specific STAT5-inhibition in BCR-ABL-positive leukemia.
Video analysis for insight and coding: Examples from tutorials in introductory physics
Rachel E. Scherr
Physical Review Special Topics. Physics Education Research , 2009,
Abstract: The increasing ease of video recording offers new opportunities to create richly detailed records of classroom activities. These recordings, in turn, call for research methodologies that balance generalizability with interpretive validity. This paper shares methodology for two practices of video analysis: (1) gaining insight into specific brief classroom episodes and (2) developing and applying a systematic observational protocol for a relatively large corpus of video data. These two aspects of analytic practice are illustrated in the context of a particular research interest but are intended to serve as general suggestions.
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