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Search Results: 1 - 10 of 1319 matches for " Melanie Kunath "
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Active Transport of the Ubiquitin Ligase MID1 along the Microtubules Is Regulated by Protein Phosphatase 2A
Beatriz Aranda-Orgillés, Johanna Aigner, Melanie Kunath, Rudi Lurz, Rainer Schneider, Susann Schweiger
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0003507
Abstract: Mutations in the MID1 protein have been found in patients with Opitz BBB/G syndrome (OS), which is characterised by multiple malformations of the ventral midline. MID1 is a microtubule-associated protein that stabilizes microtubules and, in association with the regulatory subunit of protein phosphatase 2A (PP2A), α4, provides ubiquitin ligase activity for the ubiquitin-specific modification of PP2A. Using Fluorescence Recovery After Photobleaching (FRAP) technology, we show here that MID1 is actively and bi-directionally transported along the microtubules, and that this movement is directly linked to its MAP kinase and PP2A-mediated phosphorylation status. Intact transport depends on both kinesins and dyneins and is inhibited upon colcemide treatments. MID1 proteins carrying missense mutations in the α4 binding domain still bind the microtubules but cannot be actively transported. Likewise, knock-down of the α4 protein, inhibition of PP2A activity by okadaic acid and fostriecin or the simulation of permanent phosphorylation at Ser96 in MID1 stop the migration of MID1-GFP, while preserving its microtubule-association. In summary, our data uncover an unexpected and novel function for PP2A, its regulatory subunit α4 and PP2A/α4/mTOR signaling in the active transport of the MID1 ubiquitin ligase complex along the cytoskeleton. Furthermore, a failure in the microtubule directed transport of this protein complex would be an attractive mechanism underlying the pathogenesis of OS in patients with B-box1 mutations.
Alternative polyadenylation signals and promoters act in concert to control tissue-specific expression of the Opitz Syndrome gene MID1
Jennifer Winter, Melanie Kunath, Stefan Roepcke, Sven Krause, Rainer Schneider, Susann Schweiger
BMC Molecular Biology , 2007, DOI: 10.1186/1471-2199-8-105
Abstract: Here we show that alternative polyadenylation generates the size differences observed in the Northern blot analyses. Analysis of EST data together with additional Northern blot analyses proved tissue-specific usage of the alternative polyadenylation sites. Bioinformatic characterization of the different 3'UTRs of MID1 revealed numerous RNA-protein interaction motifs, several of which turned out to be conserved between different species. Furthermore, our data suggest that mRNA termination at different polyadenylation sites is predetermined by the choice of alternative 5'UTRs and promoters of the MID1 gene, a mechanism that efficiently allows synergistic function of 5' and 3'UTRs.MID1 expression is tightly regulated through concerted action of alternative promoters and alternative polyadenylation signals both during embryonic development and in the adult.Mutations in the X-linked MID1 gene cause Opitz G/BBB syndrome (OS). OS is a congenital malformation syndrome characterized by defective ventral midline development with the main features being ocular hypertelorism and hypospadias. Additional abnormalities such as cleft lip and palate, laryngo-tracheal fistulas, heart defects, imperforate anus and mental retardation may also be present.Recently we found that the MID1 protein associates with microtubules [1] and triggers ubiquitination and degradation of the microtubule-associated protein phosphatase 2a (PP2A) upon interaction with the α4 protein [2]. MID1 loss-of-function mutations, as seen in OS patients, thus cause accumulation of microtubule-associated PP2A and hypophosphorylation of its target proteins.The MID1 mRNA is subject to extensive alternative splicing [3]. Also, several 5'-untranslated regions have been identified and the use of five alternative promoters results in the production of additional MID1 transcript isoforms [4].The expression pattern of MID1 has been investigated by Northern blot analyses and in situ hybridization [5-8]. In humans, three trans
Point Mutations in GLI3 Lead to Misregulation of its Subcellular Localization
Sybille Krau?,Joyce So,Melanie Hambrock,Andrea K?hler,Melanie Kunath,Constance Scharff,Martina Wessling,Karl-Heinz Grzeschik,Rainer Schneider,Susann Schweiger
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0007471
Abstract: Mutations in the transcription factor GLI3, a downstream target of Sonic Hedgehog (SHH) signaling, are responsible for the development of malformation syndromes such as Greig-cephalopolysyndactyly-syndrome (GCPS), or Pallister-Hall-syndrome (PHS). Mutations that lead to loss of function of the protein and to haploinsufficiency cause GCPS, while truncating mutations that result in constitutive repressor function of GLI3 lead to PHS. As an exception, some point mutations in the C-terminal part of GLI3 observed in GCPS patients have so far not been linked to loss of function. We have shown recently that protein phosphatase 2A (PP2A) regulates the nuclear localization and transcriptional activity a of GLI3 function.
Developing an educational framework for the teaching of simulation within nurse education  [PDF]
Melanie Humphreys
Open Journal of Nursing (OJN) , 2013, DOI: 10.4236/ojn.2013.34049

The use of simulations as a teaching and learning tool within health care has increasing importance; simulations are seen as the major teaching method for practicing and assessing developing skills, knowledge, attitudes and meaningful decision-making within the field of nursing. Certainly the utilisations of simulations feature widely within many aspects of health care; a greater understanding of the key conceptual notions will serve to benefit all of those engaged within their application. This literature review has enabled the construction of a conceptual model for the teaching of simulation and can serve to promote the continued positive development of simulations within education. Through a consistent and insightful approach to teaching, dynamic learning will be assured within this very important aspect of engaging the nursing student within the learning process.

ERK2 Suppresses Self-Renewal Capacity of Embryonic Stem Cells, but Is Not Required for Multi-Lineage Commitment
William B. Hamilton, Keisuke Kaji, Tilo Kunath
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0060907
Abstract: Activation of the FGF-ERK pathway is necessary for na?ve mouse embryonic stem (ES) cells to exit self-renewal and commit to early differentiated lineages. Here we show that genetic ablation of Erk2, the predominant ERK isozyme expressed in ES cells, results in hyper-phosphorylation of ERK1, but an overall decrease in total ERK activity as judged by substrate phosphorylation and immediate-early gene (IEG) induction. Normal induction of this subset of canonical ERK targets, as well as p90RSK phosphorylation, was rescued by transgenic expression of either ERK1 or ERK2 indicating a degree of functional redundancy. In contrast to previously published work, Erk2-null ES cells exhibited no detectable defect in lineage specification to any of the three germ layers when induced to differentiate in either embryoid bodies or in defined neural induction conditions. However, under self-renewing conditions Erk2-null ES cells express increased levels of the pluripotency-associated transcripts, Nanog and Tbx3, a decrease in Nanog-GFP heterogeneity, and exhibit enhanced self-renewal in colony forming assays. Transgenic add-back of ERK2 is capable of restoring normal pluripotent gene expression and self-renewal capacity. We show that ERK2 contributes to the destabilization of ES cell self-renewal by reducing expression of pluripotency genes, such as Nanog, but is not specifically required for the early stages of germ layer specification.
Approaching the Direct Object Pronouns: How Much Grammatical Form Is Necessary in Instruction?  [PDF]
Melanie L. D’Amico
Open Journal of Modern Linguistics (OJML) , 2013, DOI: 10.4236/ojml.2013.34041
Abstract: The main goal of this investigation was to determine if there is a more effective approach among focus on forms, focus on meaning, or focus on form for teaching the direct object pronouns to beginning students of Spanish. It will be beneficial to discover which of these three widely-used approaches can best help students to acquire correct pronoun use, and may aid instructors of Spanish in the teaching of these pronouns. In order to compare these approaches, three sections of a beginning Spanish course received instruction in one of the three approaches. The participants of this study were 51 beginning level students who had had 3 years of Spanish instruction at the high school level and were native speakers of English. The study follows a pretest/posttest design. Results find positive results for form-focused instruction over purely meaning-focused instruction for teaching the Spanish direct object pronouns with regards to sentence completion tasks. A main implication of this study is that focus on meaning instruction is not sufficient to help beginning learners improve their production of Spanish direct object pronouns. While results show a more positive impact for focus on form instruction over the more traditional focus on forms approach, additional research comparing these two methods is suggested. It is also important to note that beginning level learners show overall low levels of accuracy with direct object pronouns in Spanish.
Complexity of Interaction in a Second Language Conversation Group: An Exploratory Study  [PDF]
Melanie Lynn D’Amico
Open Journal of Modern Linguistics (OJML) , 2015, DOI: 10.4236/ojml.2015.54031
Abstract: The aim of this research was to explore the nature of conversation in a weekly second language Italian conversation group. Analysis of conversations focused on the range of topics and verbal structures used by learners. Additional analysis was completed to determine if learners engaged in negotiation of meaning or form during conversations. Results revealed that learners used a range of topics and verbal structures from Beginner level to Advanced level indicating that learners challenged themselves to produce high quality, natural conversation. Learners also showed some use of negotiation during conversations to repair communication breakdowns, principally to address meaning; however, the amount of negotiation was low when compared to task-based interaction designed to elicit negotiation.
Plasmacytoid variant of bladder cancer defines patients with poor prognosis if treated with cystectomy and adjuvant cisplatin-based chemotherapy
Keck Bastian,Wach Sven,Stoehr Robert,Kunath Frank
BMC Cancer , 2013, DOI: 10.1186/1471-2407-13-71
Abstract: Background Since the definition of different histologic subtypes of urothelial carcinomas by the World Health Organization (WHO) 2004 classification, description of molecular features and clinical behavior of these variants has gained more attention. Methods We reviewed 205 tumor samples of patients with locally advanced bladder cancer mainly treated within the randomized AUO-AB05/95 trial with radical cystectomy and adjuvant cisplatin-based chemotherapy for histologic subtypes. 178 UC, 18 plasmacytoid (PUC) and 9 micropapillary (MPC) carcinomas of the bladder were identified. Kaplan Meier analysis and backward multivariate Cox’s proportional hazards regression analysis were performed to compare overall survival between the three histologic subtypes. Results Patients suffering from PUC have the worst clinical outcome regarding overall survival compared to conventional UC and MPC of the bladder that in turn seem have to best clinical outcome (27.4 months, 62.6 months, and 64.2 months, respectively; p=0.013 by Kaplan Meier analysis). Backward multivariate Cox′s proportional hazards regression analysis (adjusted to relevant clinicopathological parameters) showed a hazard ratio of 3.2 (p=0.045) for PUC in contrast to patients suffering from MPC. Conclusions Histopathological diagnosis of rare variants of urothelial carcinoma can identify patients with poor prognosis.
Tamoxifen for the management of breast events induced by non-steroidal antiandrogens in patients with prostate cancer: a systematic review
Kunath Frank,Keck Bastian,Antes Gerd,Wullich Bernd
BMC Medicine , 2012, DOI: 10.1186/1741-7015-10-96
Abstract: Background Tamoxifen has emerged as a potential management option for gynecomastia and breast pain due to non-steroidal antiandrogens, and it is considered an alternative to surgery or radiotherapy. The objective of this systematic review was to assess the benefits and harms of tamoxifen, in comparison to other treatment options, for either the prophylaxis or treatment of breast events induced by non-steroidal antiandrogens in prostate cancer patients. Methods We searched CENTRAL, MEDLINE, EMBASE, reference lists, the abstracts of three major conferences and three trial registers to identify ongoing randomized controlled trials (RCTs). Two authors independently screened the articles identified, assessed the trial quality and extracted data. The protocol was prospectively registered (CRD42011001320; http://www.crd.york.ac.uk/PROSPERO). Results Four studies were identified. Tamoxifen significantly reduced the risk of suffering from gynecomastia (risk ratio 9RR0 0.10, 95% CI 0.05 to 0.22) or breast pain (RR 0.06, 95% CI 0.02 to 0.17) at six months compared to untreated controls. Tamoxifen also showed a significant benefit for the prevention of gynecomastia (RR 0.22, 95% CI 0.08 to 0.58) and breast pain (RR 0.25, 95% CI 0.10 to 0.64) when compared to anastrozole after a median of 12 months. One study showed a significant benefit of tamoxifen for the prevention of gynecomastia (RR 0.24, 95% CI 0.09 to 0.65) and breast pain (RR 0.20, 95% CI 0.06 to 0.65) when compared with radiotherapy at six months. Radiotherapy increased the risk of suffering from nipple erythema and skin irritation, but there were no significant differences for any other adverse events (all P > 0.05). Conclusions The currently available evidence suggests good efficacy of tamoxifen for the prevention and treatment of breast events induced by non-steroidal antiandrogens. The impact of tamoxifen therapy on long-term adverse events, disease progression and survival remains unclear. Further large, well-designed RCTs, including long-term follow-ups, are warranted. Also, the optimal dose needs to be clarified.
Tackling Tuberculosis in Latvia
Melanie Zipperer
PLOS Medicine , 2005, DOI: 10.1371/journal.pmed.0020122
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