895 research outputs found
Carbonic Anhydrase Inhibitors: Identifying Therapeutic Cancer Agents Through Virtual Screening
No full textComputer-aided drug design includes an ensemble of different in silico strategies that represent valuable tools for facilitating the discovery and optimization of novel hit compounds endowed with biological activity toward the desired target proteins. Due to the various pathological implications of carbonic anhydrases (CAs), especially in the development and progression of cancer, molecular modeling techniques have been widely applied for the identification of new CA inhibitors. In this chapter, after providing the reader with a brief introduction to computational methods in drug design, we summarize the results of the main virtual screening (VS) studies that led to the discovery of novel ligands of different CA isoforms, describing the various receptor-based and ligand-based approaches employed. Moreover, we report the results of retrospective analyses in which CAs and their known ligands have been used to validate the performance of various VS methods in hit identification. The present chapter should provide the reader with a panoramic view of the most used and reliable in silico techniques to be applied in the search for novel CA inhibitors
Community, self and rites of passage: the St. Francis Xavier ring ceremony
No full textThis thesis explores the concept of rites of passage as it was developed in anthropology, in the exploration and study of magico/religious ceremonies of primitive societies. It argues that for the most part the topic of rites of passage has been neglected by modern sociology. Through examination of a modern ceremony, the ring ceremony at St. Francis Xavier University (St. FX), this paper argues that there are modem examples of rites of passage and that these ceremonies have a considerable impact on one's sense of self in terms of achieving identity and acquiring perspective. The study explores the St. FX ring
ceremony from several angles. First it draws upon the experience of the researcher in a similar ceremony. Second, it uses observational research at a St. FX ring ceremony in December of 1997. Third, it uses a series of interviews with both participants of the St. FX ring ceremony and the university's administration, to gain an understanding of the ceremony, its purpose and its meaning for all involved. The study concludes that there are modem ceremonies that exhibit the components of rites of passage and that these ceremonies are useful in modem society in building both a sense of community and an
individual's sense of self
Carbonic anhydrases in higher plants: an overview
No full textCarbonic anhydrase (CA) activity in plants was first reported in 1939(Neish, 1939). Since then there have been two major periods of research; an early period in which CAs were studied using classical biochemical techniques (purification and determination of kinetic properties) and a late period in which the physiology and the molecular biology were studied. Since the early period of CA research has been reviewed (see Badger and Price, 1994; Deutsch, 1987; Poincelot, 1979) in this chapter, I will address advances in our understanding of the molecular biology and physiology of carbonic anhydrase in higher plants
Carbonic anhydrases in higher plants: an overview
No full textCarbonic anhydrase (CA) activity in plants was first reported in 1939(Neish, 1939). Since then there have been two major periods of research; an early period in which CAs were studied using classical biochemical techniques (purification and determination of kinetic properties) and a late period in which the physiology and the molecular biology were studied. Since the early period of CA research has been reviewed (see Badger and Price, 1994; Deutsch, 1987; Poincelot, 1979) in this chapter, I will address advances in our understanding of the molecular biology and physiology of carbonic anhydrase in higher plants
Identification of Two Novel Genome-Wide Significant Single Nucleotide Polymorphisms, associated with Barrett’s Oesophagus, determined by further Replication of a Genome-Wide Association Study
No full textBarrett\u27s oesophagus (BE) is a common premalignant condition to oesophageal adenocarcinoma (EAC). A previous genome-wide association study (GWAS) identified BE susceptibility Single Nucleotide Polymorphisms (SNPs) on chromosome 6p21, within the HLA region, and16q23, where the closest protein-coding gene was FOXF1. The replication study outlined in this thesis aimed to identify possible additional variants that did not reach genome-wide significance in the GWAS, in up to 10,158 BE patients and 21,062 controls. Meta-analysis of the data identified two further BE susceptibility SNPs: rs3072 (2p24.1; OR=1.14; 95%CI 1.09-1.18; P=1.8×10−11); and rs2701108 (12q24.21; OR=0.90; 95%CI 0.86-0.93; P=7.5×10−9). The two closest protein-coding genes, and most likely functional targets, are the bone morphogenetic protein pathway ligand GDF7 (rs3072) and TBX5 (rs2701108). A second GWAS of combined BE and EAC cases was recently published, analysing a total of 922,031 SNPs, where 87 of 94 associated SNPs with P\u3c1×10−4 were selected for further replication, identified four SNPs (three loci) with BE/EAC risk in CRTC1 and BARX1 and within 100kb of FOXP1. Our data supported three of the BE/EAC associated SNPs and meta-analysis of all 87 SNPs detected a further susceptibility locus, rs3784262, near ALDH1A2 (OR=0.90, 95%CI 0.87-0.93, P=3.72×10−9). Overall, two novel BE susceptibility loci have been identified and data has been provided to support three previously identified BE/EAC SNPs and one additional BE/EAC locus. To date, genes implicated in BE susceptibility appear to encode transcription factors involved in thoracic, diaphragmatic and oesophageal development or inflammatory response proteins
A multivariate analysis search for a single-top quark produced in association with missing energy in proton-proton collisions at the Large Hadron Collider at a center-of-mass energy of 221As = 8 TeV with the ATLAS detector
No full textThis dissertation presents a search for single-top quarks produced in association with missing energy, denoted as monotop, using 20.3~fb^{\mathhyphen 1} of proton-proton collision data at ~TeV recorded with the ATLAS detector. The search is conducted in two separate analyses consisting of a cut-based and a multivariate approach. As no deviation from the Standard Model prediction is observed, upper limits are set on the monotop production cross-section times branching ratio for resonant and non-resonant production of an invisible exotic state in association with a single-top quark. In the case of resonant production, for a spin-0 resonance with a mass of 500~GeV, an effective coupling strength above 0.13 is excluded at the 95\% confidence level for an invisible spin-1/2 state with mass up to 100~GeV using the cut-based approach. In the case of non-resonant production, an effective coupling strength above 0.2 is excluded at the 95\% confidence level for an invisible spin-1 state with mass up to 657~GeV and 799~GeV using the cut-based and multivariate approaches, respectively. In addition to setting observed limits at ~TeV, expected upper limits are set on the non-resonant production model for future levels of integrated luminosity expected to be recorded at ~TeV.Thesis (Ph. D.)--Michigan State University. Physics, 2017Includes bibliographical references (pages 539-546
The polymorphic variant rs1800734 influences methylation acquisition and allele-specific TFAP4 binding in the MLH1 promoter leading to differential mRNA expression
No full textExpression of the mismatch repair gene MutL homolog 1 (MLH1) is silenced in a clinically important subgroup of sporadic colorectal cancers. These cancers exhibit hypermutability with microsatellite instability (MSI) and differ from microsatellite-stable (MSS) colorectal cancers in both prognosis and response to therapies. Loss of MLH1 is usually due to epigenetic silencing with associated promoter methylation; coding somatic mutations rarely occur. Here we use the presence of a colorectal cancer (CRC) risk variant (rs1800734) within the MLH1 promoter to investigate the poorly understood mechanisms of MLH1 promoter methylation and loss of expression. We confirm the association of rs1800734 with MSI+ but not MSS cancer risk in our own data and by meta-analysis. Using sensitive allele-specific detection methods, we demonstrate that MLH1 is the target gene for rs1800734 mediated cancer risk. In normal colon tissue, small allele-specific differences exist only in MLH1 promoter methylation, but not gene expression. In contrast, allele-specific differences in both MLH1 methylation and expression are present in MSI+ cancers. We show that MLH1 transcriptional repression is dependent on DNA methylation and can be reversed by a methylation inhibitor. The rs1800734 allele influences the rate of methylation loss and amount of re-expression. The transcription factor TFAP4 binds to the rs1800734 region but with much weaker binding to the risk than the protective allele. TFAP4 binding is absent on both alleles when promoter methylation is present. Thus we propose that TFAP4 binding shields the protective rs1800734 allele of the MLH1 promoter from BRAF induced DNA methylation more effectively than the risk allele
Effect of egg turning and incubation time on carbonic anhydrase gene expression in the blastoderm of the Japanese quail (Coturnix c. japonica)
No full text(1) The gene expression of carbonic anhydrase, a key enzyme for the production sub-embryonic fluid (SEF), was assessed in turned and unturned eggs of the Japanese quail. The plasma membrane-associated isoforms CA IV, CAIX, CA XII, CA XIV, and the cytoplasmic isoform CA II, were
investigated in the extra-embryonic tissue of the blastoderm and in embryonic blood.
(2) Eggs were incubated at 37.6C, c. 60% R.H., and turned hourly (90 ) or left unturned. From 48 to 96 hours of incubation mRNA was extracted from blastoderm tissue, reverse-transcribed to cDNA and quantified by real-time qPCR using gene-specific primers. Blood collected at 96h was processed identically.
(3) Blastoderm CAIV gene expression increased with the period of incubation only in turned eggs, with maxima at 84 and 96h of incubation. Only very low levels were found in blood.
(4) Blastoderm CA II gene expression was greatest at 48 and 54h of incubation, subsequently declining to much lower levels and una ected by turning. Blood CA II gene expression was about 25-fold greater than that in the blastoderm.
(5) The expression of CA IX in the blastoderm was the highest of all isoforms, yet unaffected by turning.
CA XII did not amplify and CA XIV was present at unquantifiable low levels.
(6) It is concluded that solely gene expression for CA IV is sensitive to egg turning, and that increased CA IV gene expression could account for the additional SEF mass found at 84-96h of incubation.
in embryos of turned eggs
Immersion: Digital Collaborative Environments
No full textThis thesis investigates the potential of Virtual Reality (VR) to solve established clashes in order to improve collaboration between industry professionals, while reducing spatial confusion. Industry professionals and academics state that it is collaboration itself that is one of the most critical factors in ensuring that a construction project is successful. In recent years people have investigated VR as a tool to provide a better environment for design due to its immersive properties and training potential. Current research is primarily focussed on the technology itself, but there are few studies conducted on the people using the technology and what they need in order to do so effectively. While it is essential to further the knowledge in the technological aspect, it is also vital to ensure that people can use it to its full potential. The aim of this study is to explore the relationship between advanced technology being developed and the way that people will be using it, alongside VR’s applicability as a collaborative tool for architecture and construction projects The focus of this study. While there are companies using VR in different stages of a project, it is unknown how productive people are when using this medium and what they require in order to use the technology effectively. Initial interviews with professionals have shown that there are problems in both peoples understanding of the technology used on projects as well as the methods of Building Information Modelling (BIM). The second part of this study involved multiple experiments in which users were put in different scenarios to solve clashes in a digital model using VR and Computer Assisted Design (CAD). This was performed in groups to investigate how they used the technology as well as how they collaborated within the digital environments. Initial experiments were run in Unity without a VR headset, and the final experiment was run using a VR headset (HTC Vive) for the full immersive experience. From these interviews and multiple experiments, the results produced insight into current user issues surrounding advanced BIM technology and the best way to implement them to make full use of the technologies capability during the design phase of a project. The results provided a framework detailing the information users need when using this technology to solve clashes collaboratively. Considering level of detail within the model alongside navigation tools, and perspectives provided a reliable method for aiding users in all aspects of collaborating in digital environments.</p
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