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Bromodomain Proteins in HIV Infection
Daniela Boehm,Ryan J. Conrad,Melanie Ott
Viruses , 2013, DOI: 10.3390/v5061571
Abstract: Bromodomains are conserved protein modules of ~110 amino acids that bind acetylated lysine residues in histone and non-histone proteins. Bromodomains are present in many chromatin-associated transcriptional regulators and have been linked to diverse aspects of the HIV life cycle, including transcription and integration. Here, we review the role of bromodomain-containing proteins in HIV infection. We begin with a focus on acetylated viral factors, followed by a discussion of structural and biological studies defining the involvement of bromodomain proteins in the HIV life cycle. We end with an overview of promising new studies of bromodomain inhibitory compounds for the treatment of HIV latency.
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.

Recruitment and Activation of RSK2 by HIV-1 Tat
Claudia Hetzer, Dwayne Bisgrove, Michael S. Cohen, Angelika Pedal, Katrin Kaehlcke, Anja Speyerer, Kerstin Bartscherer, Jack Taunton, Melanie Ott
PLOS ONE , 2007, DOI: 10.1371/journal.pone.0000151
Abstract: The transcriptional activity of the integrated HIV provirus is dependent on the chromatin organization of the viral promoter and the transactivator Tat. Tat recruits the cellular pTEFb complex and interacts with several chromatin-modifying enzymes, including the histone acetyltransferases p300 and PCAF. Here, we examined the interaction of Tat with activation-dependent histone kinases, including the p90 ribosomal S6 kinase 2 (RSK2). Dominant-negative RSK2 and treatment with a small-molecule inhibitor of RSK2 kinase activity inhibited the transcriptional activity of Tat, indicating that RSK2 is important for Tat function. Reconstitution of RSK2 in cells from subjects with a genetic defect in RSK2 expression (Coffin-Lowry syndrome) enhanced Tat transactivation. Tat interacted with RSK2 and activated RSK2 kinase activity in cells. Both properties were lost in a mutant Tat protein (F38A) that is deficient in HIV transactivation. Our data identify a novel reciprocal regulation of Tat and RSK2 function, which might serve to induce early changes in the chromatin organization of the HIV LTR.
Automated Estimation of Collagen Fibre Dispersion in the Dermis and its Contribution to the Anisotropic Behaviour of Skin
Aisling Ní Annaidh,Karine Bruyère,Michel Destrade,Michael D. Gilchrist,Corrado Maurini,Melanie Otténio,Giuseppe Saccomandi
Physics , 2012, DOI: 10.1007/s10439-012-0542-3
Abstract: Collagen fibres play an important role in the mechanical behaviour of many soft tissues. Modelling of such tissues now often incorporates a collagen fibre distribution. However, the availability of accurate structural data has so far lagged behind the progress of anisotropic constitutive modelling. Here, an automated process is developed to identify the orientation of collagen fibres using inexpensive and relatively simple techniques. The method uses established histological techniques and an algorithm implemented in the MATLAB image processing toolbox. It takes an average of 15 s to evaluate one image, compared to several hours if assessed visually. The technique was applied to histological sections of human skin with different Langer line orientations and a definite correlation between the orientation of Langer lines and the preferred orientation of collagen fibres in the dermis was observed. The structural parameters of the Gasser-Ogden-Holzapfel (GOH) model were all successfully evaluated. It is expected that the results of this study will assist those wishing to model skin, and that the algorithm described will be of benefit to those who wish to evaluate the collagen dispersion of other soft tissues.
The Herpes Simplex Virus Protein pUL31 Escorts Nucleocapsids to Sites of Nuclear Egress, a Process Coordinated by Its N-Terminal Domain
Christina Funk?,Melanie Ott,Verena Raschbichler?,Claus-Henning Nagel?,Anne Binz?,Beate Sodeik?,Rudolf Bauerfeind?,Susanne M. Bailer
PLOS Pathogens , 2015, DOI: 10.1371/journal.ppat.1004957
Abstract: Progeny capsids of herpesviruses leave the nucleus by budding through the nuclear envelope. Two viral proteins, the membrane protein pUL34 and the nucleo-phosphoprotein pUL31 form the nuclear egress complex that is required for capsid egress out of the nucleus. All pUL31 orthologs are composed of a diverse N-terminal domain with 1 to 3 basic patches and a conserved C-terminal domain. To decipher the functions of the N-terminal domain, we have generated several Herpes simplex virus mutants and show here that the N-terminal domain of pUL31 is essential with basic patches being critical for viral propagation. pUL31 and pUL34 entered the nucleus independently of each other via separate routes and the N-terminal domain of pUL31 was required to prevent their premature interaction in the cytoplasm. Unexpectedly, a classical bipartite nuclear localization signal embedded in this domain was not required for nuclear import of pUL31. In the nucleus, pUL31 associated with the nuclear envelope and newly formed capsids. Viral mutants lacking the N-terminal domain or with its basic patches neutralized still associated with nucleocapsids but were unable to translocate them to the nuclear envelope. Replacing the authentic basic patches with a novel artificial one resulted in HSV1(17+)Lox-UL31-hbpmp1mp2, that was viable but delayed in nuclear egress and compromised in viral production. Thus, while the C-terminal domain of pUL31 is sufficient for the interaction with nucleocapsids, the N-terminal domain was essential for capsid translocation to sites of nuclear egress and a coordinated interaction with pUL34. Our data indicate an orchestrated sequence of events with pUL31 binding to nucleocapsids and escorting them to the inner nuclear envelope. We propose a common mechanism for herpesviral nuclear egress: pUL31 is required for intranuclear translocation of nucleocapsids and subsequent interaction with pUL34 thereby coupling capsid maturation with primary envelopment.
Activation of HIV Transcription by the Viral Tat Protein Requires a Demethylation Step Mediated by Lysine-specific Demethylase 1 (LSD1/KDM1)
Naoki Sakane,Hye-Sook Kwon,Sara Pagans,Katrin Kaehlcke,Yasuhiro Mizusawa,Masafumi Kamada,Kara G. Lassen,Jonathan Chan,Warner C. Greene,Martina Schnoelzer,Melanie Ott
PLOS Pathogens , 2011, DOI: 10.1371/journal.ppat.1002184
Abstract: The essential transactivator function of the HIV Tat protein is regulated by multiple posttranslational modifications. Although individual modifications are well characterized, their crosstalk and dynamics of occurrence during the HIV transcription cycle remain unclear. We examine interactions between two critical modifications within the RNA-binding domain of Tat: monomethylation of lysine 51 (K51) mediated by Set7/9/KMT7, an early event in the Tat transactivation cycle that strengthens the interaction of Tat with TAR RNA, and acetylation of lysine 50 (K50) mediated by p300/KAT3B, a later process that dissociates the complex formed by Tat, TAR RNA and the cyclin T1 subunit of the positive transcription elongation factor b (P-TEFb). We find K51 monomethylation inhibited in synthetic Tat peptides carrying an acetyl group at K50 while acetylation can occur in methylated peptides, albeit at a reduced rate. To examine whether Tat is subject to sequential monomethylation and acetylation in cells, we performed mass spectrometry on immunoprecipitated Tat proteins and generated new modification-specific Tat antibodies against monomethylated/acetylated Tat. No bimodified Tat protein was detected in cells pointing to a demethylation step during the Tat transactivation cycle. We identify lysine-specific demethylase 1 (LSD1/KDM1) as a Tat K51-specific demethylase, which is required for the activation of HIV transcription in latently infected T cells. LSD1/KDM1 and its cofactor CoREST associates with the HIV promoter in vivo and activate Tat transcriptional activity in a K51-dependent manner. In addition, small hairpin RNAs directed against LSD1/KDM1 or inhibition of its activity with the monoamine oxidase inhibitor phenelzine suppresses the activation of HIV transcription in latently infected T cells. Our data support the model that a LSD1/KDM1/CoREST complex, normally known as a transcriptional suppressor, acts as a novel activator of HIV transcription through demethylation of K51 in Tat. Small molecule inhibitors of LSD1/KDM1 show therapeutic promise by enforcing HIV latency in infected T cells.
Lipid Droplet-Binding Protein TIP47 Regulates Hepatitis C Virus RNA Replication through Interaction with the Viral NS5A Protein
Dorothee A. Vogt,Grégory Camus,Eva Herker,Brian R. Webster,Chia-Lin Tsou,Warner C. Greene,Tien-Sze Benedict Yen,Melanie Ott
PLOS Pathogens , 2013, DOI: 10.1371/journal.ppat.1003302
Abstract: The nonstructural protein NS5A has emerged as a new drug target in antiviral therapies for Hepatitis C Virus (HCV) infection. NS5A is critically involved in viral RNA replication that takes place at newly formed membranes within the endoplasmic reticulum (membranous web) and assists viral assembly in the close vicinity of lipid droplets (LDs). To identify host proteins that interact with NS5A, we performed a yeast two-hybrid screen with the N-terminus of NS5A (amino acids 1–31), a well-studied α-helical domain important for the membrane tethering of NS5A. Our studies identified the LD-associated host protein, Tail-Interacting Protein 47 (TIP47) as a novel NS5A interaction partner. Coimmunoprecipitation experiments in Huh7 hepatoma cells confirmed the interaction of TIP47 with full-length NS5A. shRNA-mediated knockdown of TIP47 caused a more than 10-fold decrease in the propagation of full-length infectious HCV in Huh7.5 hepatoma cells. A similar reduction was observed when TIP47 was knocked down in cells harboring an autonomously replicating HCV RNA (subgenomic replicon), indicating that TIP47 is required for efficient HCV RNA replication. A single point mutation (W9A) in NS5A that disrupts the interaction with TIP47 but preserves proper subcellular localization severely decreased HCV RNA replication. In biochemical membrane flotation assays, TIP47 cofractionated with HCV NS3, NS5A, NS5B proteins, and viral RNA, and together with nonstructural viral proteins was uniquely distributed to lower-density LD-rich membrane fractions in cells actively replicating HCV RNA. Collectively, our data support a model where TIP47—via its interaction with NS5A—serves as a novel cofactor for HCV infection possibly by integrating LD membranes into the membranous web.
Faraday Rotation Structure on Kiloparsec Scales in the Giant Radio Lobes of Centaurus A
Ilana Feain,Ronald Ekers,Tara Murphy,Bryan Gaensler,J-P Macquart,Raymond Norris,Tim Cornwell,Melanie Johnston-Hollitt,Juergen Ott,Enno Middelberg
Physics , 2009, DOI: 10.1088/0004-637X/707/1/114
Abstract: We present the results of an Australia Telescope Compact Array 1.4 GHz spectropolarimetric aperture synthesis survey of 34 square degrees centred on Centaurus A - NGC 5128. A catalogue of 1005 extragalactic compact radio sources in the field to a continuum flux density of 3 mJy/beam is provided along with a table of Faraday rotation measures (RMs) and linear polarised intensities for the 28 percent of sources with high signal-to-noise in linear polarisation. We use the ensemble of 281 background polarised sources as line-of-sight probes of the structure of the giant radio lobes of Centaurus A. This is the first time such a method has been applied to radio galaxy lobes and we explain how it differs from the conventional methods that are often complicated by depth and beam depolarisation effects. We use an RM structure function analysis and report the detection of a turbulent RM signal, with rms of 17 rad/m^2 and scale size 0.3 degrees, associated with the southern giant lobe. We cannot verify whether this signal arises from turbulent structure throughout the lobe or only in a thin skin (or sheath) around the edge, although we favour the latter. The RM signal is modelled as possibly arising from a thin skin with a thermal plasma density equivalent to the Centaurus intragroup medium density and a coherent magnetic field that reverses its sign on a spatial scale of 20 kpc.
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.
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