A probabilistic approach for cluster based polyrepresentative information retrieval

A thesis submitted to the University of Bedfordshire in partial ful lment of the requirements for the degree of Doctor of PhilosophyDocument clustering in information retrieval (IR) is considered an alternative to rank-based retrieval approaches, because of its potential to support user interactions beyond just typing in queries. Similarly, the Principle of Polyrepresentation (multi-evidence: combining multiple cognitively and/or functionally diff erent information need or information object representations for improving an IR system's performance) is an established approach in cognitive IR with plausible applicability in the domain of information seeking and retrieval. The combination of these two approaches can assimilate their respective individual strengths in order to further improve the performance of IR systems. The main goal of this study is to combine cognitive and cluster-based IR approaches for improving the eff ectiveness of (interactive) information retrieval systems. In order to achieve this goal, polyrepresentative information retrieval strategies for cluster browsing and retrieval have been designed, focusing on the evaluation aspect of such strategies. This thesis addresses the challenge of designing and evaluating an Optimum Clustering Framework (OCF) based model, implementing probabilistic document clustering for interactive IR. Thus, polyrepresentative cluster browsing strategies have been devised. With these strategies a simulated user based method has been adopted for evaluating the polyrepresentative cluster browsing and searching strategies. The proposed approaches are evaluated for information need based polyrepresentative clustering as well as document based polyrepresentation and the combination thereof. For document-based polyrepresentation, the notion of citation context is exploited, which has special applications in scientometrics and bibliometrics for science literature modelling. The information need polyrepresentation, on the other hand, utilizes the various aspects of user information need, which is crucial for enhancing the retrieval performance. Besides describing a probabilistic framework for polyrepresentative document clustering, one of the main fi ndings of this work is that the proposed combination of the Principle of Polyrepresentation with document clustering has the potential of enhancing the user interactions with an IR system, provided that the various representations of information need and information objects are utilized. The thesis also explores interactive IR approaches in the context of polyrepresentative interactive information retrieval when it is combined with document clustering methods. Experiments suggest there is a potential in the proposed cluster-based polyrepresentation approach, since statistically signifi cant improvements were found when comparing the approach to a BM25-based baseline in an ideal scenario. Further marginal improvements were observed when cluster-based re-ranking and cluster-ranking based comparisons were made. The performance of the approach depends on the underlying information object and information need representations used, which confi rms fi ndings of previous studies where the Principle of Polyrepresentation was applied in diff erent ways

A viewpoint-based case-based reasoning approach utilising an enterprise architecture ontology for experience management

The accessibility of project knowledge obtained from experiences is an important and crucial issue in enterprises. This information need about project knowledge can be different from one person to another depending on the different roles he or she has. Therefore, a new ontology-based case-based reasoning (OBCBR) approach that utilises an enterprise ontology is introduced in this article to improve the accessibility of this project knowledge. Utilising an enterprise ontology improves the case-based reasoning (CBR) system through the systematic inclusion of enterprisespecific knowledge. This enterprise-specific knowledge is captured using the overall structure given by the enterprise ontology named ArchiMEO, which is a partial ontological realisation of the enterprise architecture framework (EAF) ArchiMate. This ontological representation, containing historical cases and specific enterprise domain knowledge, is applied in a new OBCBR approach. To support the different information needs of different stakeholders, this OBCBR approach has been built in such a way that different views, viewpoints, concerns and stakeholders can be considered. This is realised using a case viewpoint model derived from the ISO/IEC/IEEE 42010 standard. The introduced approach was implemented as a demonstrator and evaluated using an application case that has been elicited from a business partner in the Swiss research project.This work was supported in part by the Commission for Technology and Innovation (CTI) of the Swiss Confederation under Grant 14575.1 PFES-ES and the ELO Digital Office CH AG.http://www.tandfonline.com/loi/teis202018-04-30hb2017Information Scienc

The importance of plant-derived lipids for arbuscular mycorrhiza symbiosis and other plant-microbe interactions

Ever since their origin, plants have been associated with diverse microorganisms, above as well as below ground. Particularly widespread and therefore prominent is the plant interaction with arbuscular mycorrhiza fungi (AMF). Arbuscular mycorrhiza (AM) is an ancient mutualistic symbiosis between most land plants and obligate biotrophic fungi of the Glomeromycotina. The key feature of this plant-microbe association is the reciprocal nutrient transfer between both organisms. Nutrient exchange in AM symbiosis (AMS) has been studied already for decades and mineral nutrients such as phosphate, ammonia and sulfate were identified as important commodities transferred from the fungus to the plant. Vice versa, hexoses have been found to be translocated from the plant to the fungus as reward. This nutrient swap has great impact on health, physiology and overall performance of the host plant. It also has effects at a much larger scale on global carbon cycles and the sustainment of complex ecosystems such as tropical rainforests. AMF colonize plant roots via an intraradical hyphal network and insert arbuscules, which are highly branched tree-shaped structures, in single inner cortical root cells. The arbuscule and its host cell represent the main interface of this association and thereby the core element, at which nutrient transfer takes place. The host plant is in control of AM root colonization by the fungus, as a range of plant mutants is available, which perturb root colonization. A number of plant AM mutants, exhibit a similar AM- phenotype, with a reduced percentage of root length colonization and a perturbed arbuscule morphology, which is characterized by small, less branched and stunted arbuscules. The two Lotus japonicus mutants dis (disorganized arbuscule) and ram2 (reduced arbuscular mycorrhiza), which are impaired in the establishment of AMS, have been identified via a forward genetics screen. Both, DIS and RAM2, are AM-specific fatty acid/lipid biosynthesis genes in Lotus japonicus. DIS encodes a b-keto-acyl ACP synthase I (KASI), crucial for fatty acid chain elongation from C4 to C16 and RAM2 encodes glycerol-3-phosphate acyltransferase 6 (GPAT6), which acts bifunctionally by catalyzing dephosphorylation as well as acylation of glycerol-3-phosphate (G3P) in order to produce sn2-monoacylglycerol (MAG). In this doctoral thesis, both genes were characterized in-depth, concerning function, expression and requirement for the symbiosis. I was able to show that AM-competent host plants harbor an AM-specific lipid biosynthesis machinery in their genomes, which is used to produce lipids exclusively in arbuscule containing cells. Strikingly, I revealed that these lipids are transported to the obligate biotrophic fungus for its nourishment. Via application of 13C6-glucose to colonized plants, followed by isotopolog profiling, I could show that plant-derived lipids are transported to the fungus in colonized L. japonicus wildtype plants. In contrast, lipid transport was perturbed in both lipid biosynthesis mutants, dis and ram2, and in the AM-specific ABCG half-transporter mutant str (stunted arbuscules). In addition, I collaborated with the laboratory of Peter Dörmann (University of Bonn) in the characterization of the AM-specific fatty acid thioesterase FatM, which terminates fatty acid chain elongation by hydrolysis of the acyl-ACP thioester bond. FatM is a further essential component of the AM-exclusive fatty acid/lipid biosynthesis machinery in arbuscocytes (arbuscule-containing cells) and acts in the same pathway with DIS and RAM2. Literature suggests that the dependence on host lipids or lipid parasitism occur in a range of interorganismic associations with participants from almost all kingdoms. By investigating the influence of plant-derived lipids on the detrimental association of Arabidopsis thaliana with the oomycete Hyaloperonospora arabidopsidis (Hpa), this thesis goes beyond the boundaries of AM research. Hpa-infected Arabidopsis thaliana mutants, which carry their mutations in KASI and GPAT6, that are homologs of DIS and RAM2, exhibited severe impairment in colonization by and development of Hpa. These results hint towards a prominent role of plant-derived lipids also for oomycete- plant interactions.Seit ihrem Ursprung sind Pflanzen mit unterschiedlichen Mikroorganismen sowohl über- als auch unterirdisch vergesellschaftet. Weit verbreitet und daher von besonderer Bedeutung ist die Interaktion von Pflanzen mit arbuskulären Mykorrhiza Pilzen (AMP). Die arbuskuläre Mykorrhiza (AM) ist eine evolutionär alte Symbiose, die zwischen den meisten Landpflanzen und den obligat-biotrophen Pilzen der Glomeromycotina ausgebildet wird. Das Hauptmerkmal dieser Pflanzen-Mikrobien- Interaktion ist der reziproke Nährstoffaustausch zwischen beiden Organismen. Der Nährstoffaustausch der arbuskulären Mykorrhiza Symbiose (AMS) wird bereits seit Jahrzenten erforscht. Hierbei wurden mineralische Nährstoffe wie Phosphat, Ammonium und Sulfat als wichtige Stoffe identifiziert, die von dem Pilz zur Pflanze transportiert werden. Als Gegenleistung wurden Hexosen ausfindig gemacht, die in entgegengesetzter Richtung von der Pflanze zum Pilz transportiert werden. Dieser Nährstoffhandel wirkt sich erheblich auf die Gesundheit, die Physiologie und das allgemeine Leistungsvermögen der Wirtspflanze aus. In einem jedoch noch größeren Ausmaß beeinflusst dieser Nährstoffaustausch außerdem globale Kohlenstoffkreisläufe und die Erhaltung komplexer Ökosysteme, wie die der tropischen Regenwälder. AMP besiedeln die Pflanzenwurzeln durch ein intraradikales Hyphennetzwerk und kolonisieren zusätzlich einzelne Wurzelzellen des inneren Kortex durch die Ausbildung von Arbuskeln (hoch-verzweigte baumförmige Strukturen). Die Schnittstelle zwischen Arbuskel und Wirtszelle stellt das Kernstück der Symbiose dar, da an dieser der Nährstoffaustausch stattfindet. Wie die Existenz einer Reihe von Pflanzenmutanten, welche die Wurzelkolonisierung beeinträchtigen, zeigt, kontrolliert die Wirtspflanze die Kolonisierung durch den Pilz. Einige pflanzliche AM-Mutanten weisen einen ähnlichen AM-Phänotypen auf, der durch eine reduzierte Wurzelkolonisierungsrate und eine gestörte Arbuskelmorphologie (kleine, gering-verzweigte und verkümmerte Arbuskeln) gekennzeichnet ist. In einem klassisch-genetischen Screen wurden die beiden Lotus japonicus Mutanten dis (disorganized arbuscules) und ram2 (reduced arbuscular mycorrhiza), welche in der Ausbildung der AMS beeinträchtigt sind, identifiziert. DIS und RAM2 sind beides AM-spezifische Fettsäure- bzw. Lipidbiosynthese Gene in Lotus japonicus. DIS kodiert für eine b-Keto-Acyl-ACP Synthase I (KASI), die für die Verlängerung der Fettsäurekette von C4 nach C16 entscheidend ist, während RAM2 für eine Glycerol- 3-Phosphat Acyltransferase 6 (GPAT6) kodiert, die durch die Katalyse der Dephosphorylierung und der Acylierung von Glycerol-3-phosphat (G3P) bifunktional wirkt, um sn2-Monoacylglycerol (MAG) herzustellen. In dieser Doktorarbeit wurden beide Gene betreffend Funktion, Expression und deren Notwendigkeit für die Symbiose charakterisiert. Es konnte herausgefunden werden, dass AM-kompetente Wirtspflanzen einen AM-spezifischen Lipidbiosyntheseweg besitzen, der genutzt wird, um Lipide ausschließlich in Arbuskel-enthaltenden Zellen zu produzieren. Außerdem konnte gezeigt werden, dass diese Lipide zum obligat- biotrophen Pilz für dessen Ernährung transportiert werden. Durch die Auswertung der Isotopolog-Profile nach der Zugabe von 13C6-Glukose zu kolonisierten Pflanzen, konnte gezeigt werden, dass in kolonisierten Lotus japonicus Wildtyp-Pflanzen pflanzliche Lipide zum Pilz transportiert werden. Im Gegensatz dazu war der Lipidtransport in beiden Lipidbiosynthesemutanten, dis und ram2, sowie in der AM- spezifischen ABCG Halb-Transporter Mutante str (stunted arbeuscues) beeinträchtigt. Drüber hinaus wurde in Kollaboration mit dem Labor von Peter Dörmann (Universität Bonn) die AM-spezifische Fettsäure-Thioesterase FatM charakterisiert, welche die Verlängerung der Fettsäurenkette mittels Hydrolyse der Acyl-ACP Thioester Bindung beendet. FatM ist eine weitere essentielle Komponente des AM-exklusiven Fettsäure- /Lipidbiosyntheseweges in Arbuskozyten (Arbuskel-enthaltende Zellen) und agiert im selben Signalweg wie DIS und RAM2. Die Fachliteratur legt nahe, dass die Abhängigkeit von Wirtslipiden bzw. das Phänomen des Lipid-Parasitismus für eine Reihe von interorganismischen Vereinigungen mit Vertretern aus fast allen Reichen bekannt ist. Durch die Erforschung des Einflusses pflanzlich-abstammender Lipide auf die schädliche Interaktion von Arabidopsis thaliana mit dem Oomyceten Hyaloperonospora arabidopsidis (Hpa), geht diese Arbeit über die AM-Forschung hinaus. Hpa-infizierte Arabidopsis Mutanten, die Mutationen in KASI bzw. GPAT6 (Homologe von DIS bzw. RAM2) tragen, wiesen eine starke Beeinträchtigung sowohl in der Kolonisierung als auch in der Entwicklung von Hpa auf. Diese Ergebnisse deuten auf eine bedeutende Rolle pflanzlicher Lipide auch für Oomyceten-Pflanzen-Interaktionen hin

Analysis of ROCK2 activation in transgenic mouse skin carcinogenesis

The purpose of this study was to investigate ROCK2 activation in squamous cell carcinogenesis and assess its co-operation with rasHa and fos oncogene activation together with loss of PTEN mediated AKT regulation. The analysis of ROCK deregulation with these genes in the MAP Kinase and PI3K pathways, two of the most commonly deregulated signalling systems, employed a well-characterised, transgenic mouse skin model of multi-stage carcinogenesis. A major goal was to study co-operation between these genes in the conversion of benign tumours to malignancy and investigate subsequent progression to aggressive carcinomas, given these are the most significant clinical stages of carcinogenesis from a patient’s viewpoint; and also investigated effects of ROCK2 deregulation on the processes of normal epidermal differentiation. ROCK2 is an effector protein of RhoA, which is a member of the ras superfamily and ROCK2 activation has been associated with tumour progression via an increase in tissue stiffness mediated by changes in actomyosin cytoskeleton leading to increased cellular motility. Thus, ROCK2 expression is commonly associated with the later events in cancer. Furthermore, there are many studies investigating ROCK2 in cancer given that it may be a useful therapeutic target in being downstream of oncogenic ras signalling. Yet, relatively few studies have explored the possibilities of a definite link that confirms the co-operation status of ROCK2 activation with ras/MAPK/fos and /or PTEN/PI3K/AKT pathways in SCC aetiology. Thus, questions exist as to exactly when does ROCK2 activation become causal; and what are the collaborating genes involved in the mechanism that drive the early or late stage events in carcinogenesis. To begin to answer these questions, inducible ROCK2 activation has been introduced into a well-characterised transgenic mouse skin carcinogenesis model that expressed a combination of ras and fos activation, driven by a modified human keratin 1 vector (HK1). Thus, exclusive epidermal expression of activated rasHa and fos oncogenes, in proliferative basal layers, gave hyperplasia and papillomatogenesis; but with no evidence of spontaneous malignant conversion. This stability of phenotype is thus ideal to assess roles for multiple transgene co-operations in the development of benign tumours and their conversion to malignancy. Hence, ROCK transgenic mice that expressed a conditionally active, 4-hydroxytamoxifen (4-HT)-regulated of human ROCK2 transgene were crossed with mice expressing activated rasHa and /or fos exclusively in epidermal transit amplifying keratinocytes (HK1.ras, HK1.fos). Inducible PTEN tumour suppressor gene mutation via exon 5 ablation (K14.Cre/D5PTENflx) and thus loss of AKT regulation was also incorporated into this model. This was achieved via deletion of exon 5 employing the RU486-mediated cre/loxP system, driven by keratin K14 promoter expression in basal layer keratinocytes. Therefore, to facilitate this investigation, a new and unpublished inducible ROCK2 system was employed in order to target the identical keratinocytes as PTEN loss. This new transgenic line of lsl.ROCKer transgenic mice employed the same 4-HT inducible ROCKer transgene but now driven by a generic CAG promoter following cre mediated ablation of the stop cassette once treated with RU486. In bi-genic K14.ROCKer/HK1.ras1205 mice, synergism between ROCK2 activation and (wound-promotion) sensitive HK1.ras1205 line showed direct co-operation and achieved malignant conversion of benign papillomas to well-differentiated squamous cell carcinoma (wdSCCs) histotypes (12 weeks of 4-HT treatment). This placed ROCK2 activity as the causal event driving malignant conversion, but in the absence of a wound promotion stimulus (loss of ear tag), papillomas did not convert. The correct papilloma context was required for ROCK to become causal proved to be the case on employing the wound insensitive HK1.ras1276 line. Here, K14.ROCKer/HK1.ras1276 mice failed to exhibit any papillomas and required the constitutive promotion stimulus from additional fos activation. Interestingly, following cessation of 4-HT, two intriguing observations were recorded. Firstly, that once bi-genic ROCK/ras1205 achieved malignancy, exogenous ROCKer expression appeared to show no involvement once squamous cell carcinomas (SCCs) progressed to poorly differentiated squamous cell carcinomas (pdSCCs), given the elevated expression of endogenous ROCK upon malignant progression. Secondly, the rapid growth of papilloma appeared upon cessation of 4-HT with highly intense p21 expression indicated the requirement of exogenous ROCK2 for malignant conversion and the possibility of a papilloma inhibition by 4-HT anti-cancer activity. Another major novel finding demonstrated ROCK2 activation could act as an initiator in co-operation with fos activation. Direct co-operation between ROCK2 and fos activation produced benign squamous papillomas yet, whereas ROCK2 activation alone induced hyperplasia as did fos activation alone at this time point, given papilloma formation in HK1.fos mice occur over 4-5 months. However, unlike deregulation of MAP Kinase signalling in bi-genic ROCK/ras1205 mice, in bi-genic ROCK/fos mice, no malignant conversion was observed due to high levels of compensatory p53/p21 expression. Thus, this bi-genic K14.cre/lsl.ROCKer/HK1.fos model suggests the requirement of additional mutation event for malignant conversion. An unexpected result appeared in bi-genic ROCK/Δ5PTENflx co-operation experiments where K14.cre/lsl.ROCKer/Δ5PTENflx cohorts exhibited epidermal hyperplasia with folded papillomatous appearance to the epidermis, but without papillomatogenesis even after seven month of period. This either indicates a weak co-operation between ROCK2 and Δ5PTENflx which may be due to the unexpected low levels of p-AKT from a compensatory increased p21 expression; and additional events needed to fill in the oncogenic gap in this bi-genic ROCK/Δ5PTENflx model, or may possibly highlight redundancy in the oncogenic hits provided by ROCK and PTEN. This latter suggest similar links exist between their normal roles in the epidermis which may be accountable for the alterations observed in keratinocyte differentiation. In both in vitro and in vivo experiments, K14.cre/lsl.ROCKer/Δ5PTENflx cohorts showed alterations in epidermal differentiation via anomalous K1 and low levels of K6 expression. Interestingly, activated ROCK2 appeared to induce or accelerate differentiation activity in K14.cre/lsl.ROCKer keratinocytes via increased K1 (early differentiation marker) and reduced K6 (proliferation marker) expression profiles. These results were consistent with in vivo data where K6 was expressed in low levels in K14.cre/lsl.ROCKer hyperplasia histotypes. In contrast, in K14.cre/lsl.ROCKer/Δ5PTENflx keratinocytes, inactivation of PTEN-mediated AKT activity may be accountable for restored keratin K6 and anomalous keratin K1 expression; as keratin K1 was expressed in a similar fashion of normal keratinocytes in K14.cre/lsl.ROCKer/fos keratinocytes. Interestingly, all tri-genic cohorts: K14.cre/lsl.ROCKer/ras1276/fos, K14.cre/lsl.ROCKer/fos/Δ5PTENflx and K14.cre/lsl.ROCKer/ras1276/Δ5PTENflx synergisms exhibited malignant conversion and /or malignant progression in all animals highlighting a novel role of ROCK2 activation. Further, the stage-specific consequences in each model in this study were shown to be influenced by p53/p21 status, where typically p53 expression disappeared in late stage papillomas yet, p21 expression persisted. This demonstrated the importance of compensatory p53/p21 expression in modulating tumour pathogenesis in all these models. Given that this study incorporated PTEN mutation, the influence of AKT activity was investigated in the SCC progression of tri-genic ROCK/ras1276/PTENflx and ROCK/fos/PTENflx cohorts; revealing a crucial antagonism between p21 and AKT. However, this study revealed that the malignancy in tri-genic ROCK/ras1276/fos cohorts was not influenced by p-AKT expression, and as this tri-genic model achieved wdSCCs only. This suggests that as the roles of ROCK in altering cytoskeletal organisation leading to increase in tissue stiffness are overlaid onto both MAP Kinase and AKT deregulation, the outcome is a very aggressive pdSCC. Thus, suggesting ROCK signalling to be a potential therapeutic target for ras/MAPK/fos pathway in carcinogenesis. Overall, this study showed the involvement of ROCK2 activation in the initiation stage for papillomatogenesis with fos oncogene, and demonstrated ROCK2 as a converter again and also in malignant progression with ras/fos/Δ5PTENflx mutations. This indicates the link of ROCK2 signalling with both MAPK and PI3K pathways, thus targeting ROCK2 would aid in development of cancer therapy