5,158 research outputs found
Transcription Factor AP-2 Regulatory Signatures in Breast Cancer
No full textPhDAP-2 transcription factors are highly conserved basic helix-span-helix proteins whose
members ((x, ß, y, S and c) are crucial regulators of bryonic development. They also
play an important role in human neoplasia. uohis ochemical studies have detected
high levels of AP-2y expression in primary tumo of breast cancer patients. This high
expression has been correlated with reduced survival in all patients and reduced survival
in an ERa positive subset treated with hormone therapy. In breast cancer cell lines, AP-
2 factors have been implicated in the regulation of the ERBB2 proto-oncogene and ERa.
In an effort to further understand the role of AP-2y in breast carcinoma, this study has
sought to identify additional AP-2 activated cellular pathways and ultimately novel
transcriptional targets for AP-2 through the use of gene expression profiling.
RNAi using three independent AP-2y targeting sequences, has been used to deplete AP-
2y levels in the ERa positive MCF-7 breast carcinoma cell line, chosen as it exclusively
expresses the AP-2y family member. Microarrays were then utilised to create an AP-2y
dependent transcription profile. Statistical comparisons between non-silencing control
siRNA and AP-2y targeting siRNA groups identified a total of 162 gene expression
changes (p<0.01). These changes implicate AP-2y in the control of cell cycle
progression and developmental signalling. Indeed a role for AP-2y in the control of cell
cycle, in particular at the GUS transition, has been verified using flow cytometry.
Several of these gene expression changes, including IGFBP3, Transgelin and
KIAA1324, have been confirmed using qPCR and immunoblotting.
Finally, elevated levels of p21 mRNA and protein have been observed following AP-2y
silencing in MCF-7 cells. Additionally, the activity of a p21 promoter reporter is
repressed following transfection with an AP-2y expression construct in HepG2 cells.
These results coupled with ChIP experiments showing AP-2y occupancy at the proximal
promoter region of p21 in cycling MCF-7 cells, implicate AP-2y in the repression of
p21 transcription and suggest a role for AP2y in- the, control of cell cycle in breast
carcinoma in part through the transcriptional repression of p21
The Treatment of Ties in AP Correlation
No full textThe Kendall tau and AP correlation coefficients are very commonly use to compare two rankings over the same set of items. Even though Kendall tau was originally defined assuming that there are no ties in the rankings, two alternative versions were soon developed to account for ties in two different scenarios: measure the accuracy of an observer with respect to a true and objective ranking, and measure the agreement between two observers in the absence of a true ranking. These two variants prove useful in cases where ties are possible in either ranking, and may indeed result in very different scores. AP correlation was devised to incorporate a top-heaviness component into Kendall tau, penalizing more heavily if differences occur between items at the top of the rankings, making it a very compelling coefficient in Information Retrieval settings. However, the treatment of ties in AP correlation remains an open problem. In this paper we fill this gap, providing closed analytical formulations of AP correlation under the two scenarios of ties contemplated in Kendall tau. In addition,we developed an R package that implements these coefficients.Best Short Paper Accepted author manuscriptMultimedia ComputingWeb Information System
Delamination Analysis of A Class of AP-PLY Composite Laminates
No full textA recently developed fiber placement architecture, AP-PLY, has been shown to give significantly improved damage tolerance characteristics of composite structures. The behavior of delaminations resulting from low speed impact damage is of particular concern. Major attention has been paid to expand current knowledge on the delamination response of simple AP-PLY composite structure and move towards in-depth understanding of the failure mechanisms behind the damage tolerance. This thesis presents the approaches to predict delamination onset and analyze delamination growth, in support of the search of the optimum woven pattern for AP-PLY composite laminates. The recovered interlaminar stress between layers combined with the maximum stress criterion determined the delamination onset of simple AP-PLY composite laminate under out-of-plane loads. 2D finite element models with cohesive elements inserted in the interfaces of woven layers have been built to evaluate the delamination initiation and propagation in the different woven patterns of simple AP-PLY composite beams. The parameters of the woven pattern, such as the woven angle, the number of woven plies, the number of straight filled plies, and the location of the woven patterns in through the thickness direction, were investigated and shown to have a significant effect on delamination creation and growth. An energy method based on beam theory was proposed to analyze the strain energy release rate (SERR) of an existing crack in an AP-PLY beam structure. The developed analytical method was implemented in isotropic materials and the obtained SERR of a crack was validated by reference results and finite element solutions. The general behavior of crack growth on the left or right crack tip was evaluated and basic trends leading to crack propagation on one side of the crack were established. A correction factor was introduced to improve the accuracy of the SERR of a small crack through the numerical calculation. The singularity of crack tip caused by dissimilar materials was investigated and was found that the inclusion of the singularity effect could increase the accuracy for small cracks. It has been shown that the neutral axis needs to be relocated to decouple the bending and membrane behavior of unsymmetrical composite laminates, thus to meet the requirement of minimizing the strain energy of the delaminated beam to calculate the SERR of a delaminated composite beam. The calculated SERR of a crack in a composite beam has been verified by comparing with a finite element model. The woven plies in AP-PLY composite laminate altered the layup and two conventional laminates with different stacking sequences were identified in an AP-PLY composite laminate based on the assumption that the resin areas were ignored. A step by step approach was developed to obtain the SERR of a crack that goes across different materials. The analytical SERR determined when two materials are used in sequence, sets the stage for optimization of AP-PLY composite laminates without taking account of the effect of the resin area. The procedure of optimization of simple AP-PLY pattern was proposed and industry may benefit for many applications. An equivalent stiffness approach was used to model regions containing resin pockets and straight or inclined composite layers. A series of three point bending tests was carried out where the failure process and loading capacity were evaluated. The methodology, procedure of optimization, philosophy outlined in this thesis might also be applied to the more complicated fully woven AP-PLY composite laminates. The work in this thesis contributes to the understanding of the behavior of AP-PLY composite laminates with delaminations
Chronic tumor necrosis factor alters T cell responses by attenuating T cell receptor signaling.
No full textStructure function analysis of blazars AP Librae and 3c279
No full textHighest Honors in AstronomyBlazars AP Librae and 3c279 are analyzed for microvariability using a technique known as structure function analysis. AP Librae was observed in April
of 2005 and 3c279 was observed in April of 2007. The data for AP Librae was
previously reduced by Andrew Collazzi and the author reduced the data for
3c279. Both sets of data were reduced using Robert Knop's data reduction
program.
The author ran structure function analysis on both sets of data. Structure function analysis is a statistical analysis run on data that is suppose to
nd timescales of variability, periodicity, and the noise type of data. Previous analysis of AP Librae confirmed mircrovariability, which also shows up in
the structure function of AP Librae. Blazar 3c279 was much quieter than AP
Librae and showed no microvariability durning any of the nights.College of Arts and ScienceDepartment of Physics and Astronom
AP-based wireless intrusion detection systems
No full textThis thesis was scanned from the print manuscript for digital preservation and is copyright the author.
Researchers can access this thesis by asking their local university, institution or public library to
make a request on their behalf. Monash staff and postgraduate students can use the link in the References field
Environmental toxicity, redox signaling and lung inflammation:the role of glutathione
No full textGlutathione (gamma-glutamyl-cysteinyl-glycine, GSH) is the most abundant intracellular antioxidant thiol and is central to redox defense during oxidative stress. GSH metabolism is tightly regulated and has been implicated in redox signaling and also in protection against environmental oxidant-mediated injury. Changes in the ratio of the reduced and disulfide form (GSH/GSSG) can affect signaling pathways that participate in a broad array of physiological responses from cell proliferation, autophagy and apoptosis to gene expression that involve H(2)O(2) as a second messenger. Oxidative stress due to oxidant/antioxidant imbalance and also due to environmental oxidants is an important component during inflammation and respiratory diseases such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, and asthma. It is known to activate multiple stress kinase pathways and redox-sensitive transcription factors such as Nrf2, NF-kappaB and AP-1, which differentially regulate the genes for pro-inflammatory cytokines as well as the protective antioxidant genes. Understanding the regulatory mechanisms for the induction of antioxidants, such as GSH, versus pro-inflammatory mediators at sites of oxidant-directed injuries may allow for the development of novel therapies which will allow pharmacological manipulation of GSH synthesis during inflammation and oxidative injury. This article features the current knowledge about the role of GSH in redox signaling, GSH biosynthesis and particularly the regulation of transcription factor Nrf2 by GSH and downstream signaling during oxidative stress and inflammation in various pulmonary diseases. We also discussed the current therapeutic clinical trials using GSH and other thiol compounds, such as N-acetyl-l-cysteine, fudosteine, carbocysteine, erdosteine in environment-induced airways disease
Study of the regulation of Fab1p, a phosphatidylinositol 3-phosphate 5 kinase in Saccharomyces cerevisiae.
No full textThe Saccharomyces cerevisiae protein Fab1p is the archetypal type III phosphatidyl inositol phosphate kinase. This family of enzymes is universal to all eukaryotes and is responsible for the synthesis of phosphatidylinositol 3,5-bisphosphate from phosphatidylinositol 3- phosphate. In S. cerevisiae , Fab1p regulates a number of cellular processes via the production of phosphatidylinositol 3,5-bisphosphate including: vacuole acidification, protein trafficking to the vacuole lumen, vacuole membrane recycling and apical bud formation. It is now clear that these processes are regulated independently however the molecular details of Fab1p regulation have yet to be identified. Using yeast two-hybrid analysis in a systematic screen with Fab1p and its domains, we have identified over 300 potential interactors. Phenotypic analyses on 17 corresponding deletion mutants of these proteins have identified 8 that display phenotypes consistent with loss of Fab1p. We have focused on Apl2p, which appears to be a bona fide activator of Fab1p. Apl2p, and Apl4p, which interacts with the Fab1p regulator Vacl4p, are part of the heterotetrameric complex AP-1 involved in clathrin mediated trafficking from the trans-Golgi network. We show that AP-1 regulates phosphatidylinositol 3,5-bisphosphate production in vivo and is required for the trafficking of the ubiquitinated cargoes CPS and Phm5p to the vacuole lumen, a process that requires Fab1p. Over-expression of Fab1p in AP-1 mutants reverts these trafficking defects. Using point mutants of AP-1 we show that these trafficking events are clathrin-dependant. AP-1 is not required for Fab1p-dependant vacuole morphology and vacuole acidity. Thus, we speculate that Fab1p is regulated by AP-1 for the maintenance of a pool of phosphatidylinositol 3,5-bisphosphate required for trafficking of cargoes to the vacuole. AP-1 is responsible for the retention of proteins at the trans-Golgi network therefore we speculate that retention to this compartment might also be a Fab1p-dependent mechanism
Early growth response genes -2 and -3 are essential for optimal immune responses
No full textThis thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.Early Growth Response Genes (EGR) is a family of four transcription factors containing a unique zinc finger domain. EGR-2 and EGR-3 are important for hindbrain development and myelination. These transcription factors are also necessary for lymphocyte function however, the mechanisms are still unclear. Previous findings have shown that EGR-2cKO mice develop lupus-like autoimmune disease with high levels of pro-inflammatory cytokines despite showing normal T and B cell proliferation after mitogenic stimulation. Therefore we established the CD2-EGR-2-/-EGR-3-/- mouse model to explore the phenotype, susceptibility to autoimmune disease and relevant lymphocyte function. We discovered that CD2-EGR-2-/-EGR-3-/- mice developed severe systemic autoimmune disease and expressed high levels of inflammatory cytokines. More importantly we discovered a novel finding that CD2-EGR-2-/-EGR-3-/- T and B cells had impaired cell proliferation after mitogenic stimulation. Further investigations revealed that the molecular mechanism defected in the T cell receptor signalling pathway is due to a dysfunction in Activator Protein-1 (AP-1). AP-1 is a heterodimeric protein composed of AP-1 family members including Jun, Atf and Fos. Our data shows that EGR-2 and EGR-3 directly bind with the Atf family member Batf, which prevents Batf’s inhibitory function on AP-1 activation. This research demonstrates that EGR-2 and EGR-3 intrinsically regulate chronic inflammation and also positively regulate antigen receptor activation. In conclusion EGR-2 and EGR-3 are essential for providing optimal immune responses, whilst limiting inflammatory immunopathology. We propose that this new model could be used for studying autoimmune disease
The Quest for Deeper Learning and Engagement in Advanced High School Courses
No full text· GLEF and a research team from the University of Washington worked with Washington\u27s Bellevue School District to develop and assess the impact of project-based learning on upper-level courses in high school.
· Research suggests that Advanced Placement (AP) courses may focus too much on accelerated content at the expense of deeper conceptual learning.
· The number of students taking AP courses has grown, but along with this the number failing has increased. GLEF and the research team tested project-based learning (PBL) to counteract this trend.
· Results after two years are promising. Students in the PBL-AP courses are performing as well or better than students in traditional AP courses.
· Other education funders are encouraged to use an iterative design process, work with a diverse design team, and bring in partners who can contribute needed expertise and resources
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