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Arnold, William Kenneth. "INSIGHTS INTO KEY GENE REGULATORY NETWORKS IN BORRELIA BURGDORFERI." UKnowledge, 2018. https://uknowledge.uky.edu/microbio_etds/19.
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Gene regulatory networks are composed of interconnected regulatory nodes created by regulatory factors of multiple types. All organisms finely tune gene expression in order to adapt to and survive within their current niche. Obligate parasitic bacteria are under extreme pressure to quickly and appropriately adapt their gene regulatory programs in order to survive within their given host. Borrelia burgdorferi is one such organism and persists in nature by alternating between two hosts; Ixodes spp. ticks and small vertebrate animals. These two hosts represent drastically different environments; requiring a unique gene regulatory program to survive and transmit between them. Microbiologists have long sought to better understand exactly what stimuli pathogens sense and how that information is relayed in to physiologic adaptation.
In this work I aimed to examine two parts of this interesting field. First, I sought to better understand the stimuli B. burgdorferi sense in order to adapt to their hosts by testing several hypotheses centered on the general notion that B. burgdorferi senses both internal and external metabolic cues as primary signals for adaptation. I demonstrated that a second messenger system immediately downstream of a critical metabolic pathway is important during vertebrate infection and that a key regulator of virulence is itself regulated by a factor involved in DNA replication.
Second, I sought to better define the topology of gene regulatory networks, known and unknown, that are important for the ability of the bacteria to adapt. The work in this section focus on the idea that B. burgdorferi gene regulatory networks are extremely complex and are not currently well defined in the literature. My studies revealed that B. burgdorferi possesses a large number of previously undefined regulatory targets, including extended 5’ and 3’ UTRs of known genes, and encodes several hundred-putative small non-coding RNAs. Furthermore, I demonstrate that two essential regulatory factors share substantial, independent, overlap in their regulons highlighting the still undefined complexity of regulatory networks at play in B. burgdorferi.
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Castiglione, Arcangelo. "New Insights on cryptographic hierarchical access control: models, schemes and analysis." Doctoral thesis, Universita degli studi di Salerno, 2016. http://hdl.handle.net/10556/2489.
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2014 - 2015Nowadays the current network-centric world has given rise to several security concerns regarding the access control management, which en- sures that only authorized users are given access to certain resources or tasks. In particular, according to their respective roles and respon- sibilities, users are typically organized into hierarchies composed of several disjoint classes (security classes). A hierarchy is characterized by the fact that some users may have more access rights than others, according to a top-down inclusion paradigm following speci c hier- archical dependencies. A user with access rights for a given class is granted access to objects stored in that class, as well as to all the de- scendant ones in the hierarchy. The problem of key management for such hierarchies consists in assigning a key to each class of the hierar- chy, so that the keys for descendant classes can be e ciently obtained from users belonging to classes at a higher level in the hierarchy. In this thesis we analyze the security of hierarchical key assignment schemes according to di erent notions: security with respect to key indistinguishability and against key recovery [4], as well as the two recently proposed notions of security with respect to strong key in- distinguishability and against strong key recovery [42]. More precisely, we rst explore the relations between all security notions and, in par- ticular, we prove that security with respect to strong key indistin- guishability is not stronger than the one with respect to key indistin- guishability. Afterwards, we propose a general construction yielding a hierarchical key assignment scheme that ensures security against strong key recovery, given any hierarchical key assignment scheme which guarantees security against key recovery. Moreover, we de ne the concept of hierarchical key assignment schemes supporting dynamic updates, formalizing the relative secu- rity model. In particular, we provide the notions of security with respect to key indistinguishability and key recovery, by taking into ac- count the dynamic changes to the hierarchy. Furthermore, we show how to construct a hierarchical key assignment scheme supporting dy- namic updates, by using as a building block a symmetric encryption scheme. The proposed construction is provably secure with respect to key indistinguishability, provides e cient key derivation and updat- ing procedures, while requiring each user to store only a single private key. Finally, we propose a novel model that generalizes the conventional hierarchical access control paradigm, by extending it to certain addi- tional sets of quali ed users. Afterwards, we propose two construc- tions for hierarchical key assignment schemes in this new model, which are provably secure with respect to key indistinguishability. In par- ticular, the former construction relies on both symmetric encryption and perfect secret sharing, whereas, the latter is based on public-key threshold broadcast encryption. [edited by author]
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Ramió, Pujol Sara. "Insights into key parameters for bio-alcohol production in syngas fermentation using model carboxydotrophic bacteria." Doctoral thesis, Universitat de Girona, 2016. http://hdl.handle.net/10803/388041.
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This doctoral thesis deals with the synthesis of two biofuels (bioethanol and biobuthanol) by bacteria. Concretely, the thesis is focused on a group of bacteria able to grow in a simple substrate such as synthesis gas or syngas. Syngas is a mixture of hydrogen, carbon monoxide, and carbon dioxide obtained through the gasification of urban and forestry wastes. The use of syngas as a substrate requires a good knowledge of bacterial metabolism to successfully control acid production and promote alcohol synthesis. To acquire this knowledge, the researcher carried out a set of experiments at lab scale, always using syngas. Among the most significant results, there is the relevance of both the temperature and the bacteria state at the start of the experiments. Additionally, new insights into bacterial metabolism which are applicable at industrial scale were gathered.Aquesta tesi doctoral tracta la producció de dos biocombustibles – el bioetanol i el bioalcohol - per mitjà de microorganismes. En concret, la tesi s'ha centrat en un grup de bacteris capaços de sintetitzar bioalcohols a partir del gas de síntesis o syngas. El syngas és una mescla d’hidrogen, diòxid de carboni i monòxid de carboni que s’obté mitjançant la gasificació de diferents tipus de residus. L’ús d’aquest gas com a substrat requereix un bon coneixement del metabolisme dels bacteris involucrats a fi de controlar amb èxit la producció d'àcids i afavorir la d'alcohols. Aquest coneixement s'ha adquirit amb una sèrie d'experiments avançats a escala de laboratori. Entre els resultats més significatius destaca la rellevància que ha demostrat tenir la temperatura en què creixen els bacteris i l’estat del bacteri en el moment d’inici dels experiments. També s’han aportat nous coneixements sobre el metabolisme bacterià que són aplicables a escala industrial.
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De, Pais Paiva Santos Catarina. "Insights into the mechanisms of TAFA4 : a key player in modulating injury-induced mechanical pain." Thesis, Aix-Marseille, 2020. http://www.theses.fr/2020AIXM0241.
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La douleur chronique représente un problème médical majeur et les thérapies actuelles sont souvent inefficaces et présentent des effets secondaires indésirables. Récemment, notre équipe a identifié une nouvelle molécule pour le traitement de la douleur chronique : TAFA4. Ce neuropeptide d’une centaine d’acide-aminé est sécrété par une sous-population de neurones des ganglions de la racine dorsale appelés mécanorécepteurs à bas seuil de type C (C-LTMR). Nous avons montré que TAFA4 réverse l'hypersensibilité mécanique induite par une lésion de type inflammatoire, neuropathique ou post-opératoire. Cet effet anti-nociceptif de TAFA4 passe par l’intermédiaire du récepteur LRP1 (Low density lipoprotein receptor-related protein). Nous avons validé biochimiquement et fonctionnellement le rôle de LRP1 dans l’action de TAFA4. Par ailleurs, nous avons identifié une sous-population d'interneurones inhibiteurs dans la couche laminaire II interne de la corne dorsale de la moelle épinière qui présentent une augmentation du courant potassique transitoire de type A et une diminution du courant h suite à un modèle de douleur neuropathique. De façon intéressante, nous montrons que TAFA4 permet de reverser cette modulation des courants et que cette réversion est bloquée par un antagoniste de LRP1. Mes travaux montrent que TAFA4 est un nouveau et puissant antalgique et que les C-LTMR sont des acteurs cruciaux dans la modulation des mécanismes douloureux. Ces résultats mettent en évidence, pour la première fois, des mécanismes moléculaires et cellulaires qui étayent une des théories les plus débattues dans le domaine de la douleur, « The Gate Control Theory of Pain»Chronic pain denotes a major worldwide medical problem with current therapies being ineffective and often displaying adverse side effects. Recently, our group identified the secreted neuropeptide TAFA4 as a novel candidate for treating chronic pain. Specifically, we showed that TAFA4 is highly expressed in a subpopulation of dorsal root ganglion neurons called C-low threshold mechanoreceptors, that project into the inner laminaII (LIIi) of the dorsal horn of the spinal cord. TAFA4 reverses injury-induced mechanical hypersensitivity after inflammation, and nerve injury, and increases the frequency of spontaneous inhibitory postsynaptic currents in LIIi. Here, we show that TAFA4 reverses inflammatory, neuropathic and postoperative-induced mechanical hypersensitivity, and that the analgesic effect of TAFA4 is mediated via the low density lipoprotein receptor-related protein (LRP1), which, when removed from the cell surface using its antagonist receptor associated protein, blocks the effect of TAFA4. Also, we identified a subpopulation of inhibitory interneurons in LIIi (LIIi-IhIN) that display an increase of the A-type transient potassium current and decrease of outward h-current after spared nerve injury. Bath application of TAFA4 modulates and reverses these currents, and this effect can be negated by blocking LRP1. Our findings highlight TAFA4 as a new powerful painkiller, in addition to contributing to the understanding of the Gate Control Theory of Pain, through the identification of a novel spinal cord circuit mediating a cross talk between C-LTMRs, LRP1 and a subset of LIIi-IhIN that modulate injury-induced loss of inhibition and the establishment of pain
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Arcamone, Dominic. "A dialectical engagement with key symbols of religiously motivated violence through the insights of Bernard Lonergan." Thesis, Australian Catholic University, 2013. https://acuresearchbank.acu.edu.au/download/93b3c1a9e23d0c0c3f0721680b284653158d67776d646cb1a7541a4790087913/1688697/ARCAMONE_Dominic_2013.pdf.
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The aim of this thesis is to dialectically engage key symbols of religiously motivated violence through the insights of Bernard Lonergan. The scope of the thesis covers four symbols: cosmic war, martyrdom, demonisation and warrior empowerment. These symbols are employed by sociologists such as Mark Juergensmeyer and psychologists such as James Jones to argue the link between religion and violence. They have also been used by the RAND group, a non-profit think tank, through its National Security Division framing an understanding of terrorism through the metaphor of cosmic war. Each of these symbols when interpreted empirically connects warfare, religion and social order. Religion is viewed more as part of the problem and not part of the solution to violence.
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Weng, Zhuangfeng, Yuan Shang, Deqiang Yao, Jinwei Zhu, and Rongguang Zhang. "Structural analyses of key features in the KANK1·KIF21A complex yield mechanistic insights into the cross-talk between microtubules and the cell cortex." AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2018. http://hdl.handle.net/10150/626562.
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The cross-talk between dynamic microtubules and the cell cortex plays important roles in cell division, polarity, and migration. A critical adaptor that links the plus ends of microtubules with the cell cortex is the KANK N-terminal motif and ankyrin repeat domains 1 (KANK1)/kinesin family member 21A (KIF21A) complex. Genetic defects in these two proteins are associated with various cancers and developmental diseases, such as congenital fibrosis of the extraocular muscles type 1. However, the molecular mechanism governing the KANK1/KIF21A interaction and the role of the conserved ankyrin (ANK) repeats in this interaction are still unclear. In this study, we present the crystal structure of the KANK1 center dot KIF21A complex at 2.1 angstrom resolution. The structure, together with biochemical studies, revealed that a five-helix-bundle-capping domain immediately preceding the ANK repeats of KANK1 forms a structural and functional supramodule with its ANK repeats in binding to an evolutionarily conserved peptide located in the middle of KIF21A. We also show that several missense mutations present in cancer patients are located at the interface of the KANK1 center dot KIF21A complex and destabilize its formation. In conclusion, our study elucidates the molecular basis underlying the KANK1/KIF21A interaction and also provides possible mechanistic explanations for the diseases caused by mutations in KANK1 and KIF21A.
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Rabi, Márton [Verfasser], and Hervé [Akademischer Betreuer] Bocherens. "New Insights into the Origin and Phylogeny of Cryptodiran Turtles Based on Key Fossil Taxa from the Mesozoic of Asia / Márton Rabi ; Betreuer: Hervé Bocherens." Tübingen : Universitätsbibliothek Tübingen, 2014. http://d-nb.info/1196878269/34.
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Rabi, Márton Verfasser], and Hervé [Akademischer Betreuer] [Bocherens. "New Insights into the Origin and Phylogeny of Cryptodiran Turtles Based on Key Fossil Taxa from the Mesozoic of Asia / Márton Rabi ; Betreuer: Hervé Bocherens." Tübingen : Universitätsbibliothek Tübingen, 2014. http://d-nb.info/1196878269/34.
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Ghanem, Ali [Verfasser], and Stefan [Akademischer Betreuer] Wölfl. "On the Regulation and Multiple Functions of the Key Gluconeogenic Enzyme Fbp1 in Rapidly Proliferating Cells: Insights from Yeast and Breast Cancer Cells / Ali Ghanem ; Betreuer: Stefan Wölfl." Heidelberg : Universitätsbibliothek Heidelberg, 2018. http://d-nb.info/1177149605/34.
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Ravanpay, Ali Cyrus. "Insights into the molecular interactions of the neurogenic basic helix-loop-helix transcription factor, neuroD2, and the mechanism of regulation of a key target, RE-1 silencing transcription factor /." Thesis, Connect to this title online; UW restricted, 2007. http://hdl.handle.net/1773/10628.
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Cash-Gibson, Lucinda 1984. "Where, why and how scientific knowledge on health inequalities is generated? : An integrated perspective to strengthen understanding of health inequalities research capacities : Key insights from the United Kingdom and the city of Barcelona." Doctoral thesis, Universitat Pompeu Fabra, 2020. http://hdl.handle.net/10803/670109.
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This dissertation aims to understand where, why and how scientific knowledge on health inequalities is produced, why and how some places have strong capacity to produce this, and what determines this capacity. It consists of five main research articles, which integrate diverse disciplinary perspectives and methods (e.g. bibliometric and network analyses; critical review, realist explanatory case studies, with semi-structured interviews and data triangulation). Results found significant inequalities within the health inequalities scientific research field, and propose a global hypothesis on the health inequalities research production process at the local/national level, and some of the potenital conditions, determinants and dynamics involved. In the case of the United Kingdom, and the city of Barcelona, evidence suggests that six causal mechanisms, when activated under certain conditions, are key contributors to the generation of a high volume of health inequalities research. Further research should confirm and analyse them in other settings.Esta disertación tiene como objetivo comprender dónde, por qué y cómo se produce el conocimiento científico sobre desigualdades en salud, e identificar qué determina la capacidad para crear este conocimiento en distintos contextos. Incluye cinco artículos de investigación que integran diversas perspectivas y métodos (análisis bibliométricos y de redes; revisión crítica; estudios de casos explicativos realistas; entrevistas semiestructuradas; y triangulación de datos). Los resultados principales señalan importantes desigualdades en la producción de conocimiento científico en desigualdades en salud a nivel global; se plantea una hipótesis global sobre dicho proceso y los principales determinantes, dinámicas y condiciones implicados a nivel local o nacional; en el caso del Reino Unido y Barcelona, la evidencia sugiere que seis mecanismos causales han contribuido a la generación de un alto volumen de investigación sobre desigualdades en salud, los cuales se activan bajo ciertas condiciones. Investigaciones futuras deberán analizar dichos mecanismos y determinantes en distintos entornos.
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Dias, de Sousa Joana Manuela [Verfasser], Michael [Akademischer Betreuer] Lalk, Michael [Gutachter] Lalk, and Wolfgang [Gutachter] Eisenreich. "Insights into the metabolic responses of Bacillus subtilis to the absence of the key signal metabolites pyruvate and UDP-glucose / Joana Manuela Dias de Sousa ; Gutachter: Michael Lalk, Wolfgang Eisenreich ; Betreuer: Michael Lalk." Greifswald : Universität Greifswald, 2019. http://d-nb.info/1194162908/34.
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Dias, de Sousa Joana Manuela [Verfasser], Michael [Akademischer Betreuer] Lalk, Michael Gutachter] Lalk, and Wolfgang [Gutachter] [Eisenreich. "Insights into the metabolic responses of Bacillus subtilis to the absence of the key signal metabolites pyruvate and UDP-glucose / Joana Manuela Dias de Sousa ; Gutachter: Michael Lalk, Wolfgang Eisenreich ; Betreuer: Michael Lalk." Greifswald : Universität Greifswald, 2019. http://nbn-resolving.de/urn:nbn:de:gbv:9-opus-30212.
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Dias, de Sousa Joana Manuela [Verfasser], Michael Akademischer Betreuer] Lalk, Michael [Gutachter] Lalk, and Wolfgang [Gutachter] [Eisenreich. "Insights into the metabolic responses of Bacillus subtilis to the absence of the key signal metabolites pyruvate and UDP-glucose / Joana Manuela Dias de Sousa ; Gutachter: Michael Lalk, Wolfgang Eisenreich ; Betreuer: Michael Lalk." Greifswald : Universität Greifswald, 2019. http://d-nb.info/1194162908/34.
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Hughes, Sheila. "Being in the body : an assessment of the extent to which the spiritual/interior experiences arising from examples of human physical activity can be interpreted/clarified through the use of concept of embodiment (informed and enriched by insights from religious studies) as an interpretive key." Thesis, St Mary's University, Twickenham, 1998. http://epubs.surrey.ac.uk/769/.
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This thesis, inter-disciplinary in nature and orientation, seeks to assess the extent to which the spiritual/interior experiences arising from specific examples of human physical activity can be interpreted/clarified through the use of the concept of embodiment (informed and enriched by insights arising from religious studies) as an interpretive key. Diversity of attitudes to the body, evident in theoretical and practical variations, necessitates a clear definition of the particular understanding of embodiment which underpins this study, an indication of how embodiment when used as a 'key' might assist in the interpretation of the experiences to be investigated, and an explanation of the process by which the critical question was identified and developed. In order to provide the methodological framework, Chapter 1 clarifies the synthesis of personal experience, practical knowledge and theoretical understandings which underpin and authenticate a research method characterised by a process of journeying 'back and forth' between key 'pieces' of evidence. In the second chapter of the study the experience arising from human physical activity is discussed and possible modes of interpretation considered. Embodiment as a key for this experience is examined in relation to sport (Chapter 3). Chapter 4 is a survey of understandings of embodiment, drawn largely from religious sources. Thereafter, in Chapter 5, sacred dance will be considered. In Chapter 6, I refer to circumstances, situations and experiences which may impede and distort the recognition and celebration of the fact of our embodiment as experienced in and through our bodies. Findings support the use of embodiment as a viable 'key' for experiences arising from certain types of human physical activity. Fully celebrated and assessed anew for different contexts, embodiment may prove to be a predominant motif of our time, redeeming and enriching our sense of what it means to be in our bodies.
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Smith, Kerry Johanna. "The relationship between insight and violence in psychosis : a systematic review, &, The predictive validity of the HCR20v3 within Scottish forensic inpatient facilities : a closer look at key dynamic variables." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28682.
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Introduction: Poor insight is included as a risk factor for violence in risk assessment tools such as the Historical Clinical Risk-Management-20 version 3 (HCR-20v3) yet there is a lack of consensus around the relationship between poor insight and violence in individuals with psychosis. A systematic literature review was therefore carried out to clarify this relationship. Relatedly, a research project aimed to outline the predictive validity of the HCR-20v3 total and sub-scale scores to violence in forensic inpatients. A secondary aim was to understand the predictive ability of 2 dynamic risk factors within the HCR-20v3 clinical sub-scale; insight and positive symptoms, alongside age and history of violence in relation to violence in psychosis. Method: A systematic search of studies investigating insight and violence in patients with psychosis, published between 1980 and 2016 was carried out on relevant databases.17 articles from combined search results of 5694, met the inclusion criteria. These were selected for full-text review and quality grading which was subject to inter-rater reliability. In the research project, the predictive validity of the HCR-20v3 to violence was assessed in N=167 forensic inpatients. A sub-sample of N=135 was then used to investigate insight, positive symptoms, age and history of violence in relation to violence. Data was extracted from case files, with the exception of violence data which was collected prospectively from date of HCR-20v3 publication via DATIX. Results: The systematic review found 8 studies in support of a positive relationship between poor insight and violence, whilst 9 studies did not support this relationship. The majority of better quality studies measured the clinical insight dimension which tended to demonstrate a positive relationship between poor insight and violence. Methodological limitations were apparent across studies. The research project found HCR-20v3 total and clinical and risk-management sub-scale scores to predict violence. The clinical sub-scale was the strongest predictor of violence and physical violence specifically. Sub-sample analysis found positive symptoms and history of violence to significantly predict violence generally whilst only positive symptoms demonstrated prediction of physical violence. Insight and age were not significantly associated with either violence type. Discussion: The systematic review found partial support for a positive relationship between poor insight and violence in psychosis. Future good quality research is required to develop a fuller understanding of this issue. Research project results support the use of the HCR-20v3 in the risk assessment and management of forensic inpatients. They reinforce the usefulness of dynamic risk factors within the clinical sub-scale in particular. In line with the majority of studies within the systematic review however, a relationship between insight and violence in a sub-sample of patients with psychosis was not found. Recommendations are made for the regular re-assessment of dynamic risk factors within the HCR-20v3 clinical sub-scale in order to support patients to reduce their level of risk, with the caveat that future research is still required to support a relationship between insight and violence in this patient group.
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Leung, Jonathan H. "Cysteine Dioxygenase: The Importance of Key Residues and Insight into the Mechanism of the Metal Center." Connect to this title, 2008. http://scholarworks.umass.edu/theses/148/.
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Drouhet, Willie. "Study of the Far Infrared Emission of Nearby Spiral Galaxies." Phd thesis, Université Paris Sud - Paris XI, 2013. http://tel.archives-ouvertes.fr/tel-00929963.
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In my PHD work I explored the links between the physical properties of interstellar dust and other components of nearby spiral galaxies especially their stellar content. I worked on 46 disk galaxies from KINGFISH with IRAC/MIPS/PACS/SPIRE maps (3.6 - 500 microns). A bias is usually introduced in estimating disk orientations by using only a single surface brightness isophote. Thus I devised different surface brightness levels separated by constant steps in surface brightness and extracted isophotes at these levels in all FIR maps as well as in all IRAC 4.5 microns maps. To further assess the coherence of the shapes of isophotes across galactic disks, I built a quantitative indicator of the difference in shape between two ellipses with same center and same semi-major axis.I defined an acceptable level of difference between isophote shapes, by comparing disk orientations found in litterature. Using this level, I found regions inside the galactic disks where the isophotal shapes are similar. From these, I extracted one disk orientation per wavelength band. I found in the vast majority of the disk galaxy maps, be it dominated by stellar or dust emission, that a large fraction of the isophotes I extracted are coherent with the idea of an underlying disk. Comparing, for each galaxy, disk orientations extracted at all wavelengths, I found evidence in 20 galaxies out of 46, that on radial ranges as large as 1/3 of the visible disk (as measured by R25), the shapes of isophotes are morphologically similar. Thus for these 20 galaxies I devised consistent disk orientations both for the stellar and dust content. These 20 galaxies are less luminous, less emitting in the IR w.r.t. the optical, less barred, and characterized by later stage types than average. I also found that the disk orientations devised by my photometric method yield results more similar to H-alpha kinematic orientations than other photometric studies based on a single isophote level.Using the orientations I found and H-alpha dynamics disk orientations, I averaged azimuthally surface brightnesses to produce radial spectral energy distributions (SED) profiles. Once fitted with a cosmic dust emission model, they resulted in radial profiles of dust and stellar content properties. I found the dust intercepted power to be proportionnal to the product of the total dust mass and the average ISRF shining on dust. This former quantity is better correlated with the bolometric stellar luminosity than any of the dust mass or the dust heating ISRF separately. Thus the old stellar populations may be an important heating source for dust. The power intercepted by dust is also very well correlated with the total infrared power. The dust intercepts a larger quantity of power coming from stars in more actively star forming galaxies.Dust exhibit radial mass surface density profiles less well described by Sersic functions than stellar ones. When both profiles are well fitted by Sersic functions, stellar density profiles have smaller half mass radii than the isophotal optical radius (R25) separately in later type galaxies, but also in more quiescent galaxies. Sersic index and half mass radius distributions have larger widths for dust than for stellar surface density profiles.I also found that the ratio of dust over stellar surface density is an important factor to explain the variations with galactic morphological type of the ratio of dust intercepted power over the power emitted by old stellar populations. This later link could be intertwined with spiral structure strength in stage types later than 2.
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Nagel, Birgit [Verfasser], and Kay-Christian [Akademischer Betreuer] Emeis. "Insights into Nitrogen and Particle Cycling in Marine Oxygen Minimum Zones / Birgit Nagel. Betreuer: Kay-Christian Emeis." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2014. http://d-nb.info/1051935601/34.
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Herrmann, Nicole [Verfasser], Matthias [Akademischer Betreuer] [Gutachter] Zabel, and Kay-Christian [Gutachter] Emeis. "Holocene climate variability and its feedbacks to hydrology and vegetation dynamics in South Africa: Insights from compound-specific stable carbon (d13C) and hydrogen (dD) isotopes / Nicole Herrmann ; Gutachter: Matthias Zabel, Kay-Christian Emeis ; Betreuer: Matthias Zabel." Bremen : Staats- und Universitätsbibliothek Bremen, 2017. http://d-nb.info/1132757088/34.
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Hamy, Anne-Sophie. "Identification of Factors Predicting Sensitivity or Resistance to Neoadjuvant Chemotherapy in Breast Cancer Neoadjuvant treatment : the future of patients with breast cancer Neoadjuvant treatment for intermediate/high-risk HER2-positive and triple-negative breast cancers: no longer an “option” but an ethical obligation Long-term outcome of the REMAGUS 02 trial, a multicenter randomised phase II trial in locally advanced breast cancer patients treated with neoadjuvant chemotherapy with or without celecoxib or trastuzumab according to HER2 status BIRC5 (survivin) : a pejorative prognostic marker in stage II/III breast cancer with no response to neoadjuvant chemotherapy Beyond Axillary Lymph Node Metastasis, BMI and Menopausal Status Are Prognostic Determinants for Triple-Negative Breast Cancer Treated by Neoadjuvant Chemotherapy Pathological complete response and prognosis after neoadjuvant chemotherapy for HER2-positive breast cancers before and after trastuzumab era: results from a real-life cohort The presence of an in situ component on pre-treatment biopsy is not associated with response to neoadjuvant chemotherapy for breast cancer Chemosensitivity, tumor infiltrating lymphocytes (TILs), and survival of postpartum PABC patients treated by neoadjuvant chemotherapy Lymphovascular invasion after neoadjuvant chemotherapy is strongly associated with poor prognosis in breast carcinoma New insight for pharmacogenomics studies from the transcriptional analysis of two large-scale cancer cell line panels Biological network-driven gene selection identifies a stromal immune module as a key determinant of triple-negative breast carcinoma prognosis A Stromal Immune Module Correlated with the Response to Neoadjuvant Chemotherapy, Prognosis and Lymphocyte Infiltration in HER2-Positive Breast Carcinoma Is Inversely Correlated with Hormonal Pathways Stromal lymphocyte infiltration after neoadjuvant chemotherapy is associated with aggressive residual disease and lower disease-free survival in HER2-positive breast cancer Interaction between molecular subtypes, stromal immune infiltration before and after treatment in breast cancer patients treated with neoadjuvant chemotherapy COX2/PTGS2 Expression Is Predictive of Response to Neoadjuvant Celecoxib in HER2-negative Breast Cancer Patients Celecoxib With Neoadjuvant Chemotherapy for Breast Cancer Might Worsen Outcomes Differentially by COX-2 Expression and ER Status: Exploratory Analysis of the REMAGUS02 Trial Comedications influence immune infiltration and pathological response to neoadjuvant chemotherapy in breast cancer." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS129.
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La chimiothérapie néoadjuvante (CNA) est utilisée dans les cancers du sein agressifs ou localement avancés (CS). Au delà des bénéfices cliniques, elle représente une opportunité pour monitorer in vivo la sensibilité d’une tumeur à un traitement.A partir de l’analyse de sets de données de patients traités par CNA, nous souhaitons identifier des mécanismes associes à la résistance ou sensibilité au traitement. Dans la première partie, nous avons évalué des paramètres, cliniques, anatomopathologiques et transcriptomiques. Nous avons démontré que des éléments non explorés comme la présence d’embols après CNA revêtaient une information pronostique importante. Dans une 2ème partie, nous avons analysé l’impact de l’infiltrat immunitaire dans le cancer du sein, et avons décrit les changements observés entre des échantillons avant et après CNA. Nous avons montré que l’impact pronostique des TILs était différent avant et après CNA, et était opposé dans les CS triple négatif ou HER2-positif. Finalement, nous avons analysé l’impact des comédications pendant la CNA. Nous avons trouvé des effets positifs – via l’augmentation de l’infiltrat immunitaire et la réponse au traitement – et des effets négatifs avec des effets délétères dans certains sous groupes de patients. En conclusion, la situation néoadjuvante représente une plateforme pour générer et potentiellement valider des hypothèses de recherche. La mise à disposition de jeux de données de patients traités par chimiothérapie néoadjuvante constituerait une ressource majeure pour accélérer la recherche contre le cancer du seinNeoadjuvant chemotherapy (NAC i.e. chemotherapy before surgery) is increasingly being used for aggressive or locally advanced breast cancer (BCs). Beyond clinical benefits, it represents an opportunity to monitor in vivo sensitivity to treatment. Based on the analysis of datasets of BCs patients treated with NAC, we aimed at identifying mechanisms associated with resistance or sensitivity to treatment.In the first part, we evaluated biological, clinical, pathological and transcriptomic patterns. We demonstrated that unexplored pathological features such as post-NAC lymphovascular invasion may carried an important prognostic information.In a second part, we analyzed impact of imune infiltration in BC and we described extensively the changes of tumor infiltrating lymphocytes (TILs) between pre and post-NAC samples. We showed that the prognostic impact of TILs was different before and after NAC, and was opposite in TNBC and HER2-positive BCs. Finally, we investigated the impact of comedications use during NAC. We found both positive effects - while enhancing immune infiltration and response to treatment - and negative effects with deleterisous oncologic outcomes in specific patients subgroups. In conclusion, the neoadjuvant setting represents a platform to both generate and potentially validate research hypotheses aiming at increasing the efficacy of treatment. The public release of real-life datasets of BC patients treated with NAC would represent a major resource to accelerate BC research
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JINDAL, TANUJ. "MANAGEMENT DASHBOARD- KEY INSIGHTS." Thesis, 2016. http://dspace.dtu.ac.in:8080/jspui/handle/repository/17033.
Full textAbstract:
Each company and firm to be safe in competitive environment should lead by good decision. For
decision making the most important things are data. By gathering data, decision maker can
analyze and make best decision. Firms can be intelligence if uses some approaches to make data
to information then to knowledge. One the most important approaches is to use a BI platform for
gathering and analyzing data.
In this project, we are trying to identify key insights into the management dashboard
performance measures across various industries.
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Bryant, Katelyn. "Reading Instruction on YouTube: Insights from Searches on Five Key Reading Topics." Thesis, 2012. http://hdl.handle.net/1807/33635.
Full textAbstract:
The recognition that YouTube, a free-access video sharing website, is being widely used as a source of public information has lead medical researchers to conduct studies on health-related videos. However, it appears that educational researchers have not explored YouTube videos about reading instruction, given that no published studies could be located on this topic. The current study conducted controlled searches related to the “big five” areas of early elementary reading instruction as identified by the National Reading Panel (phonemic awareness, phonics, fluency, vocabulary, and text comprehension). Search results were recorded and the top 40 “most relevant” videos on each topic were analyzed to determine information about viewership, format, content, and creators of the videos. Results indicated that while YouTube videos addressing all five areas of reading instruction were prolific and highly viewed, users would need to be critical, informed, and tech-savvy in order to find relevant videos from credible sources.
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Gonçalves, Céline Saraiva. "Deciphering key roles of WNT6 in glioblastoma: mechanistic, functional, and clinical insights." Doctoral thesis, 2018. http://hdl.handle.net/1822/59418.
Full textAbstract:
Tese de Doutoramento em Ciências da SaúdeMalignant gliomas are one of the deadliest cancers worldwide, for which no curative treatment is yet available. Patients with glioblastoma (GBM), the most frequent and malignant form of glioma, present a median overall survival of approximately 15 months after diagnosis. This is mainly due to the poor and unpredictable response to the standard-of-care therapy that includes radio- and chemotherapy, after surgical resection. To improve the clinical management of these patients, several efforts are being made to molecularly characterize gliomas, which would allow to improve patients’ stratification, develop targeted therapies and thus improve patients’ clinical outcome. However, the mechanisms underlying glioma pathophysiology are still underexplored, hampering the identification of new therapeutic targets. Alterations in signaling pathways required to preserve the embryonic determination may play an important role in the tumorigenic process. The WNT pathway has been described to influence nearly all aspects of embryonic development, from a single cell – establishing its polarity – to an organism – specifying the entire body axis. At the cellular level, the WNT pathway regulates cell motility, apoptosis and their capacity to self-renew. In adults, the WNT pathway is responsible for tissue homeostasis, which might explain why its aberrant activation has been reported in several tumor types, including GBM. In tumor cells, the WNT pathway has been implicated in tumor initiation, growth, invasion, metastasis, immune evasion, stem cell capacity, and therapy resistance. In humans, there are 19 WNT ligands capable of activating the WNT pathway and with nearly unique roles in development. Among them, WNT6 was recently associated with chemoresistance in gastric and bladder cancers, poor prognosis of esophageal squamous cell carcinoma and osteosarcoma patients, and increased risk to develop colorectal adenoma. However, nothing was known about the relevance of WNT6 in gliomas. This thesis aimed to unveil the relevance of WNT6 in GBM, particularly focusing on the mechanisms regulating its expression, its downstream effector signaling pathways, and its clinical significance in GBM patients. We demonstrated that WNT6 is significantly overexpressed in GBM when compared to lower-grade gliomas, independently of IDH mutations and 1p/19q co-deletion status, and in a gene-dosage independent manner. Moreover, WNT6 expression was associated with increased GBM cell viability, proliferation, invasion, migration, glioma stem cell capacity, and resistance to temozolomidebased chemotherapy, implicating WNT6 as an important oncogenic factor in glioma. Using in vivo intracranial GBM mice models with both WNT6 overexpressing and silencing GBM cell models, we demonstrated that WNT6-high tumors presented increased features of tumor aggressiveness, which was ultimately associated with mice shorter overall survival. Moreover, we identified the WNT/β-catenin, SFK and STAT3 pathways as WNT6-mediated signaling mechanisms in GBM. The association between WNT6 and stem cell markers or key cancer related pathways was also confirmed in GBM patients. Importantly, in GBM patients from several independent datasets, WNT6 was a strong prognostic biomarker of shorter overall survival, independently of other well-known prognostic factors. Since the first step for the design of new targeted therapies requires not only the identification of new molecular targets but also the understanding of their activation mechanisms, we further investigated the potential upstream regulators underlying WNT6 overexpression in glioma. We showed that DNA methylation of specific regions in the WNT6 locus regulates its expression in glioma. Additionally, we observed that HOXA9, an oncogenic transcription factor in GBM, is co-expressed with WNT6 in gliomas. Interestingly, we found that HOXA9 directly binds to the WNT6 promoter region, transcriptionally activating its expression. Thus, WNT6 DNA methylation and HOXA9 are upstream regulators of WNT6 expression in gliomas, creating new hints for innovative therapeutic approaches. In conclusion, the work summarized in this thesis describes WNT6 as a novel critical oncogene in human GBM and identifies its upstream regulators (DNA methylation and HOXA9) and downstream molecular mechanisms (namely WNT, SFK and STAT3 pathways), which may have an impact on prognostic stratification and in the design of novel attractive therapeutic options for this deadly disease.
Os gliomas malignos são um dos cancros mais mortíferos a nível mundial, para os quais não existe ainda um tratamento curativo. Pacientes com glioblastoma (GBM), o tipo de glioma mais maligno e frequente, apresentam uma sobrevida de aproximadamente 15 meses após o diagnóstico. Este facto deve-se maioritariamente à resposta fraca e imprevisível que estes pacientes apresentam quando tratados com a terapia convencional, que inclui radio- e quimioterapia após ressecção cirúrgica do tumor. Ao longo dos últimos anos, têm-se efetuado esforços no sentido de caracterizar molecularmente os gliomas de forma a melhorar a estratificação dos pacientes, desenvolver terapias direcionadas e, deste modo, melhorar o seu tratamento. Contudo, os mecanismos subjacentes à sua fisiopatologia estão ainda pouco explorados, o que impede a identificação de novos alvos terapêuticos. Alterações em vias de sinalização celulares necessárias para a embriogénese poderão ter um papel fundamental no processo tumorigénico. Em específico, a via WNT controla diversos aspetos do desenvolvimento embrionário, desde a definição da polaridade de uma única célula num tecido até à especificação do eixo corporal de um organismo. Ao nível celular, a via WNT regula a motilidade, a apoptose e a capacidade de autorrenovação. Em adultos, a via WNT é responsável pela homeostasia dos tecidos, o que pode explicar o facto da sua ativação aberrante ter sido observada em diversos tipos tumorais, incluindo GBM. Em células tumorais, a via WNT tem vindo a ser associada com a iniciação, o crescimento, a invasão, a metastização, a evasão imune, a capacidade de células estaminais e a resistência à terapia do tumor. Em humanos, existem 19 ligandos da via WNT capazes de a ativar, os quais têm um papel singular no desenvolvimento. Entre estes, o WNT6 foi recentemente associado com a resistência à quimioterapia em cancro do intestino e da bexiga, com o pior prognóstico de pacientes com carcinoma de células escamosas do esôfago e osteossarcoma, e com o risco aumentado para desenvolver adenomas colorretais. Contudo, nada se sabe acerca da relevância do WNT6 em gliomas. Esta tese tem por objetivo desvendar a relevância do WNT6 em GBM, focando particularmente nos mecanismos que regulam a sua expressão, nas vias de sinalização efetoras da sua ação, e na sua significância clínica em pacientes com GBM. Para tal, demonstrou-se que o WNT6 está significativamente sobre-expresso em GBM quando comparado a gliomas de menor grau, independentemente da existência de mutações nos genes IDH ou da co-delecção 1p/19q, e independentemente do número de cópias de ADN. Além disso, a expressão de WNT6 foi associada com o aumento da viabilidade celular, proliferação, invasão, migração, capacidade de células estaminais de glioma e resistência à quimioterapia baseada em temozolomida, estabelecendo o WNT6 como um importante fator oncogénico em glioma. Com recurso a modelos GBM intracraniais em ratinho e usando modelos de células de GBM com expressão de WNT6 diferencial, demonstrou-se que tumores com maior expressão de WNT6 apresentam um aumento de características associadas à agressividade tumoral, sendo observado uma menor sobrevida destes ratinhos. Além disso, identificamos as vias de sinalização WNT/β-catenina, SFK e STAT3 como potenciais mecanismos de sinalização mediados pelo WNT6 em GBM. A associação entre WNT6 e marcadores de células estaminais ou vias relacionadas com cancro foi ainda corroborada em pacientes com GBM. Com recurso a várias bases de dados independentes de pacientes com GBM, mostrou-se que o WNT6 é um forte biomarcador de prognóstico, associado com a menor sobrevida dos pacientes, e independente de outros fatores de prognóstico bem conhecidos. Uma vez que o primeiro passo para o desenho de novas terapias direcionadas requer não só a identificação de novos alvos moleculares, mas também a compreensão dos seus mecanismos de ativação, foram ainda investigados os potenciais mecanismos reguladores responsáveis pelo aumento da expressão do WNT6 em glioma. Por um lado, mostrou-se que a metilação do ADN em regiões específicas do locus do WNT6 regula a sua expressão em glioma. Por outro lado, observou-se que o HOXA9, um fator de transcrição oncogénico em GBM, está co-expresso com o WNT6 em gliomas. De facto, demonstrou-se que o HOXA9 se liga diretamente à região promotora do WNT6, ativando transcripcionalmente a sua expressão. Deste modo, tanto a metilação do ADN ao nível do WNT6 como o HOXA9 são potenciais reguladores da expressão do WNT6 em glioma, e podem assim ser utilizados para o desenvolvimento de abordagens terapêuticas inovadoras. Em suma, este trabalho descreve o WNT6 como um novo oncogene em GBM humano, identificando alguns dos mecanismos que regulam a sua expressão (a metilação do ADN e o HOXA9), bem como os mecanismos moleculares que são responsáveis pela sua ação (nomeadamente, as vias de sinalização WNT, SFK e STAT3). Deste modo, os resultados obtidos poderão ter um impacto crucial na estratificação prognóstica dos pacientes com GBM, e na conceção de novas opções terapêuticas mais atrativas para esta doença altamente mortífera.
The work presented in this thesis was performed in the Life and Health Sciences Research Institute (ICVS), Minho University. Financial support was provided by grants from the Foundation for Science and Technology - FCT (SFRH/BD/92786/2013), Fundação Calouste Gulbenkian, and Liga Portuguesa Contra o Cancro; by FEDER funds through the Operational Programme Competitiveness Factors - COMPETE and National Funds through FCT under the project POCI-01-0145-FEDER-007038; and by the projects NORTE-01-0145-FEDER-000013, NORTE-01-0246-FEDER-000012, and NORTE-01-0145- FEDER-000023 supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF).
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Wißmann, Corinna Sarah. "Key determinants for the slow pace of smart home adoption : a study of digital consumer insights." Master's thesis, 2020. http://hdl.handle.net/10400.14/29729.
Full textAbstract:
The smart home concept has been on the market for several years now. Its intelligent technology promises to improve living quality by enriching the consumer’s daily life with more convenience and time. Yet, it has failed to establish in the homes of mass-market consumers. Existing academic research already spend time examining the concept and its barriers. Nevertheless, empirical evidence about insights from a consumer perspective is still scarce, even though it is considered to be crucial information for facilitating the implementation and acceptance of new technology concepts. The underlying dissertation aims to understand consumer attitudes and opinions towards the topic in order to discover the reasons hindering the smart home adoption. Therefore, an online netnography was conducted. Results identify numerous pain points that are deeply anchored in the product itself: technological problems, system complexity, investment efforts, and trust issues among others. It is now the responsibility of the businesses in the industry to cooperate and to solve first and foremost the problem of interoperability among devices by establishing industry standards. Simultaneously, the usage must be simplified so that all consumers, also those who are not technology affine, are able to intuitively use the products. Additionally, companies must focus on building trust, reinforcing transparency and assuring cybersecurity.O conceito de casa inteligente já está no mercado há vários anos. A sua tecnologia inteligente promete melhorar a qualidade de vida, enriquecendo o dia-a-dia do consumidor com mais comodidade e tempo. No entanto, não conseguiu estabelecer-se nas casas dos consumidores do mercado de massas. As pesquisas acadêmicas existentes já passam o tempo examinando o conceito e suas barreiras. No entanto, as evidências empíricas sobre insights do ponto de vista do consumidor ainda são escassas, ainda que sejam consideradas informações cruciais para facilitar a implementação e aceitação de novos conceitos tecnológicos. A dissertação subjacente visa compreender as atitudes e opiniões dos consumidores em relação ao tema, a fim de descobrir as razões que dificultam a adoção de uma casa inteligente. Por isso, foi realizada uma netnografia online. Os resultados identificam inúmeros pontos de dor profundamente ancorados no próprio produto: problemas tecnológicos, complexidade do sistema, esforços de investimento e questões de confiança, entre outros. Agora é responsabilidade das empresas da indústria cooperar e resolver, antes de tudo, o problema da interoperabilidade entre dispositivos, estabelecendo padrões da indústria. Simultaneamente, o uso deve ser simplificado para que todos os consumidores, também aqueles que não são afins tecnológicos, sejam capazes de usar intuitivamente os produtos. Além disso, as empresas devem se concentrar na construção da confiança, reforçando a transparência e garantindo a segurança cibernética.
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Parimal, Kumar *. "Insights Into The Mechanistic Details Of The M.Tuberculosis Pantothenate Kinase : The Key Regulatory Enzyme Of CoA Biosynthesis." Thesis, 2009. https://etd.iisc.ac.in/handle/2005/1976.
Full textAbstract:
Tuberculosis (TB), caused by Mycobacterium tuberculosis, has long been the scourge of humanity, claiming millions of lives. It is the most devastating infectious disease of the world in terms of mortality as well as morbidity (WHO, 2009). The lack of a uniformly effective vaccine against TB, the development of resistance in the Mycobacterium tuberculosis against the present antitubercular drugs and its synergy with AIDS has made the situation very alarming. This therefore necessitates a search for new antitubercular drugs as well as the identification of new and unexplored drug targets (Broun et aI., 1992). Coenzyme A is an essential cofactor for all organisms and is synthesized in organisms from pantothenate by a universally conserved pathway (Spry et al., 2008; Sassetti and Rubin, 2003). The first enzyme of the pathway, pantothenate kinase catalyzes the most important step of the biosynthetic process, being the first committed step of CoA biosynthesis and the one at which all the regulation takes place (Gerdes et aI., 2002)
This thesis describes the successful cloning of PanK from Mycobacterium tuberculosis, its expression in E. coli, single step affinity purification, and complete biochemical and biophysical characterization. In this work, pantothenol, a widely believed inhibitor of pantothenate kinase, has been shown to act as a substrate for the mycobacterial pantothenate kinase. Further it was shown that the product, 4'phosphopantothenol, thus formed, inhibited the next step of the CoA biosynthesis pathway in vitro. The study was extended to find outthe fate of pantothenol inside the cell and it was demonstrated that the CoA biosynthetic enzymes metabolized the latter into the pantothenol derivative of CoA which then gets incorporated into acyl carrier protein. Lastly, it was decisively shown that pantothenate kinase is not only regulated by feedback inhibition by CoA but, also regulated through feed forward
stimulation by Fructose 1, 6 biphosphate (FBP), a glycolytic intermediate. The binding site of FBP was determined by docking and mutational studies of MtPanK.
Chapter 1 presents a brief survey of the literature related to Coenzyme A biosynthesis pathway and describes the objective of the thesis. It also presents a history of TB and briefly reviews literature describing TB as well as the life cycle, biology, survival strategy, mode of infection and the metabolic pathways operational in the TB parasite, Mycobacterium tuberculosis. The chapter details the enzymes involved in CoA biosynthesis pathway from various organims.
Chapter 2 In this chapter, cloning of the ORF (Rv1092c), annotated as pantothenate kinase in the Tuberculist database (http://genolist.pasteur.frfTubercuList), its expression in E. coli and purification
using affinity chromatography has been described. Protein identity was confirmed by MALDI-TOF and by its ability to complement the pantothenate kinase temperature sensitive mutant, DV70. This chapter also illustrates the oligomeric
status of MtPanK in solution and describes the biochemical characterization of MtPanK by means of two different methods, spectrophotometrically by a coupled assay and calorimetrically by using Isothermal Titration Calorimetry. Feedback inhibition of MtPanK by CoA is also discussed in this chapter.
Chapter 3 describes the biophysical characterization of MtPanK. It discusses the enthalpy (~H) and free energy change (~G) accompanying the binding of a non-hydrolysable analogue of ATP; CoA; acetyl CoA and malonyl-CoA to MtPanK. The chapter details the energetics observed upon ATP binding to pantothenate-saturated MtPanK further elucidating the order of the reaction. This chapter also describes the various strategies which were designed and tested to remove CoA from the enzyme as the latter is always purified from the cell in conjunction with CoA. Validation of these strategies for complete CoA removal (by studying the n value from ITC studies) is further described.
Chapter 4 discusses the interaction of the well-studied inhibitor of pantothenate kinases from other sources (e.g. the malarial parasite), pantothenol, with the mycobacterial enzyme. In order to investigate the interaction of this
compound with MtPanK, its effect on the kinetic reaction carried out by the enzyme was studied by several methods. Surprisingly, a new band corresponding to 4'phosphopantothenol appeared when the reaction mix of MtPanK with pantothenol and ATP was separated on TLC. The identity of the new spot was confirmed by mass spectrometry analyses of the MtPanK reaction mixture.. These findings established the fact that pantothenol is a substrate of pantothenate kinase. To delve deeper into the mechanism of interaction of this compound with the enzymes of the coenzyme A biosynthesis pathway, the ability of pantothenol to serve as a substrate for the next step of the pathway, MtCoaBC was studied. Using various approaches it was established that pantothenol is actually a substrate for the MtPanK and the inhibition observed earlier (Saliba et aI., 2005) is actually due to the inability of CoaBC to utilize 4' -phosphopantothenol as substrate.
Chapter 5 takes the story from Chapter 4 further detailing the effects of pantothenol on cultures of E. coli and M. smegmatis. I observed that pantothenol does not inhibit the culture of E. coli or M. smegmatis. So, further studies were carried out to know the fate of pantothenol once it is converted into 4'phosphopantothenoi. Since, the next enzyme of the pathway does not utilize 4'phosphopantothenol, I checked the further downstream enzyme of the pathway, CoaD, and found that it converts 4'-phosphopantothenol to thepantothenol derivative of dephospho-CoA. The next enzyme of the pathway, CoaE, took up this pantothenol derivative of dephospho-CoA as a substrate and converted it to the pantothenol derivative of CoA which was then transferred to apo-ACP by holo-ACP synthase. The holo-ACP thus synthesized enters into the dedicated pathway of fatty acid synthesis.
Extensive investigations have been carried out on the regulation of pantothenate kinases, by the product of the pathway, Coenzyme A and its thioesters,
xx establishing the latter as the feedback regulators of these enzymes. In order to
determine if the cell employs mechanisms to sense available carbon sources and consequently modulate its coenzyme A levels by regulating activity of the enzymes involvedin CoA biosynthesis, glycolytic intermediates were tested against MtPanK for their possible role in the regulation of MtPanK activity. Chapter 6 details my identification of a novel regulator of MtPanK activity, fructose-I, 6-bisphosphate (FBP), a glycolytic intermediate, which enhances the MtPanK catalyzed phosphorylation of pantothenate by three fold. Further, the possible mechanisms through which FBP mediates MtPanK activation are also discussed. This chapter also describes the experiments carried out to identify the binding site of FBP on MtPariK.Interestingly, docking of FBP on MtPanK revealed that FBP binds close to the ATP binding site on the enzyme with one of its phosphates overlapping with the 3'~phosphate of CoA thereby validating its competitive binding relative to CoA on MtPanK. Based on these observations I propose that the binding of FBP to MtPanK lowers the activation energy of pantothenate phosphorylation by PanK.
Chapter 7 presents a summary of the findings of this work. Coenzyme A biosynthesis pathway harbors immense potential in the development of drug against many communicable diseases, thanks to its essentiality for the pathogens and the differences between the pathogen and host CoA biosynthetic enzymes. The work done in this thesis extensively characterizes the first committed enzyme of the CoA biosynthetic pathway, pantothenate kinase, from Mycobacterium tuberculosis (MtPanK). The thesis also deals with the fate of a known inhibitor of PanK and proves it as a substrate for MtPanK. Finally this thesis describes a new link between glycolysis and CoA biosynthesis.
Biotin, like coenzyme A, is another essential cofactor required by several enzymes in critical metabolic pathways. De novo synthesis of this critical metabolite has been reported only in plants and microorganisms. Therefore targeting the synthesis of biotin in the tubercular pathogen is another effective means of handicapping the tubercle pathogen. During the course of my studies, I also investigated the mycobacterial biotin biosynthesis pathway, studying the first enzyme of the pathway, 7-keto-8-aminopelargonic acid (KAPA) synthase (bioF) in extensive detail. Appendix 1 elucidates the kinetic properties of 7-keto-8aminopelargonic acid synthase (bioF) from Mycobacterium tuberculosis and proves beyond doubt that D-alanine which has previously been reported to act as a competitive inhibitor for the B. sphaericus enzyme (Ploux et al., 1999), is actually a substrate for the mycobacterial bioF.
27
Parimal, Kumar *. "Insights Into The Mechanistic Details Of The M.Tuberculosis Pantothenate Kinase : The Key Regulatory Enzyme Of CoA Biosynthesis." Thesis, 2009. http://etd.iisc.ernet.in/handle/2005/1976.
Full textAbstract:
Tuberculosis (TB), caused by Mycobacterium tuberculosis, has long been the scourge of humanity, claiming millions of lives. It is the most devastating infectious disease of the world in terms of mortality as well as morbidity (WHO, 2009). The lack of a uniformly effective vaccine against TB, the development of resistance in the Mycobacterium tuberculosis against the present antitubercular drugs and its synergy with AIDS has made the situation very alarming. This therefore necessitates a search for new antitubercular drugs as well as the identification of new and unexplored drug targets (Broun et aI., 1992). Coenzyme A is an essential cofactor for all organisms and is synthesized in organisms from pantothenate by a universally conserved pathway (Spry et al., 2008; Sassetti and Rubin, 2003). The first enzyme of the pathway, pantothenate kinase catalyzes the most important step of the biosynthetic process, being the first committed step of CoA biosynthesis and the one at which all the regulation takes place (Gerdes et aI., 2002)
This thesis describes the successful cloning of PanK from Mycobacterium tuberculosis, its expression in E. coli, single step affinity purification, and complete biochemical and biophysical characterization. In this work, pantothenol, a widely believed inhibitor of pantothenate kinase, has been shown to act as a substrate for the mycobacterial pantothenate kinase. Further it was shown that the product, 4'phosphopantothenol, thus formed, inhibited the next step of the CoA biosynthesis pathway in vitro. The study was extended to find outthe fate of pantothenol inside the cell and it was demonstrated that the CoA biosynthetic enzymes metabolized the latter into the pantothenol derivative of CoA which then gets incorporated into acyl carrier protein. Lastly, it was decisively shown that pantothenate kinase is not only regulated by feedback inhibition by CoA but, also regulated through feed forward
stimulation by Fructose 1, 6 biphosphate (FBP), a glycolytic intermediate. The binding site of FBP was determined by docking and mutational studies of MtPanK.
Chapter 1 presents a brief survey of the literature related to Coenzyme A biosynthesis pathway and describes the objective of the thesis. It also presents a history of TB and briefly reviews literature describing TB as well as the life cycle, biology, survival strategy, mode of infection and the metabolic pathways operational in the TB parasite, Mycobacterium tuberculosis. The chapter details the enzymes involved in CoA biosynthesis pathway from various organims.
Chapter 2 In this chapter, cloning of the ORF (Rv1092c), annotated as pantothenate kinase in the Tuberculist database (http://genolist.pasteur.frfTubercuList), its expression in E. coli and purification
using affinity chromatography has been described. Protein identity was confirmed by MALDI-TOF and by its ability to complement the pantothenate kinase temperature sensitive mutant, DV70. This chapter also illustrates the oligomeric
status of MtPanK in solution and describes the biochemical characterization of MtPanK by means of two different methods, spectrophotometrically by a coupled assay and calorimetrically by using Isothermal Titration Calorimetry. Feedback inhibition of MtPanK by CoA is also discussed in this chapter.
Chapter 3 describes the biophysical characterization of MtPanK. It discusses the enthalpy (~H) and free energy change (~G) accompanying the binding of a non-hydrolysable analogue of ATP; CoA; acetyl CoA and malonyl-CoA to MtPanK. The chapter details the energetics observed upon ATP binding to pantothenate-saturated MtPanK further elucidating the order of the reaction. This chapter also describes the various strategies which were designed and tested to remove CoA from the enzyme as the latter is always purified from the cell in conjunction with CoA. Validation of these strategies for complete CoA removal (by studying the n value from ITC studies) is further described.
Chapter 4 discusses the interaction of the well-studied inhibitor of pantothenate kinases from other sources (e.g. the malarial parasite), pantothenol, with the mycobacterial enzyme. In order to investigate the interaction of this
compound with MtPanK, its effect on the kinetic reaction carried out by the enzyme was studied by several methods. Surprisingly, a new band corresponding to 4'phosphopantothenol appeared when the reaction mix of MtPanK with pantothenol and ATP was separated on TLC. The identity of the new spot was confirmed by mass spectrometry analyses of the MtPanK reaction mixture.. These findings established the fact that pantothenol is a substrate of pantothenate kinase. To delve deeper into the mechanism of interaction of this compound with the enzymes of the coenzyme A biosynthesis pathway, the ability of pantothenol to serve as a substrate for the next step of the pathway, MtCoaBC was studied. Using various approaches it was established that pantothenol is actually a substrate for the MtPanK and the inhibition observed earlier (Saliba et aI., 2005) is actually due to the inability of CoaBC to utilize 4' -phosphopantothenol as substrate.
Chapter 5 takes the story from Chapter 4 further detailing the effects of pantothenol on cultures of E. coli and M. smegmatis. I observed that pantothenol does not inhibit the culture of E. coli or M. smegmatis. So, further studies were carried out to know the fate of pantothenol once it is converted into 4'phosphopantothenoi. Since, the next enzyme of the pathway does not utilize 4'phosphopantothenol, I checked the further downstream enzyme of the pathway, CoaD, and found that it converts 4'-phosphopantothenol to thepantothenol derivative of dephospho-CoA. The next enzyme of the pathway, CoaE, took up this pantothenol derivative of dephospho-CoA as a substrate and converted it to the pantothenol derivative of CoA which was then transferred to apo-ACP by holo-ACP synthase. The holo-ACP thus synthesized enters into the dedicated pathway of fatty acid synthesis.
Extensive investigations have been carried out on the regulation of pantothenate kinases, by the product of the pathway, Coenzyme A and its thioesters,
xx establishing the latter as the feedback regulators of these enzymes. In order to
determine if the cell employs mechanisms to sense available carbon sources and consequently modulate its coenzyme A levels by regulating activity of the enzymes involvedin CoA biosynthesis, glycolytic intermediates were tested against MtPanK for their possible role in the regulation of MtPanK activity. Chapter 6 details my identification of a novel regulator of MtPanK activity, fructose-I, 6-bisphosphate (FBP), a glycolytic intermediate, which enhances the MtPanK catalyzed phosphorylation of pantothenate by three fold. Further, the possible mechanisms through which FBP mediates MtPanK activation are also discussed. This chapter also describes the experiments carried out to identify the binding site of FBP on MtPariK.Interestingly, docking of FBP on MtPanK revealed that FBP binds close to the ATP binding site on the enzyme with one of its phosphates overlapping with the 3'~phosphate of CoA thereby validating its competitive binding relative to CoA on MtPanK. Based on these observations I propose that the binding of FBP to MtPanK lowers the activation energy of pantothenate phosphorylation by PanK.
Chapter 7 presents a summary of the findings of this work. Coenzyme A biosynthesis pathway harbors immense potential in the development of drug against many communicable diseases, thanks to its essentiality for the pathogens and the differences between the pathogen and host CoA biosynthetic enzymes. The work done in this thesis extensively characterizes the first committed enzyme of the CoA biosynthetic pathway, pantothenate kinase, from Mycobacterium tuberculosis (MtPanK). The thesis also deals with the fate of a known inhibitor of PanK and proves it as a substrate for MtPanK. Finally this thesis describes a new link between glycolysis and CoA biosynthesis.
Biotin, like coenzyme A, is another essential cofactor required by several enzymes in critical metabolic pathways. De novo synthesis of this critical metabolite has been reported only in plants and microorganisms. Therefore targeting the synthesis of biotin in the tubercular pathogen is another effective means of handicapping the tubercle pathogen. During the course of my studies, I also investigated the mycobacterial biotin biosynthesis pathway, studying the first enzyme of the pathway, 7-keto-8-aminopelargonic acid (KAPA) synthase (bioF) in extensive detail. Appendix 1 elucidates the kinetic properties of 7-keto-8aminopelargonic acid synthase (bioF) from Mycobacterium tuberculosis and proves beyond doubt that D-alanine which has previously been reported to act as a competitive inhibitor for the B. sphaericus enzyme (Ploux et al., 1999), is actually a substrate for the mycobacterial bioF.
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Sousa, Ricardo Jorge Silva. "Key exploited species as surrogates for coastal conservation in an oceanic archipelago: insights from topshells and limpets from Madeira (NE Atlantic Ocean)." Doctoral thesis, 2020. http://hdl.handle.net/10400.13/2858.
Full textAbstract:
As lapas e os caramujos estão entre os herbívoros mais bem adaptados ao intertidal do Atlântico
Nordeste. Estas espécies-chave fornecem serviços ecossistémicos valiosos, desempenhando um papel
fundamental no equilíbrio ecológico do intertidal e têm um elevado valor económico, estando sujeitas
a altos níveis de exploração e representando uma das atividades económicas mais rentáveis na pesca
de pequena escala no arquipélago da Madeira. Esta dissertação visa preencher as lacunas existentes
na história de vida e dinâmica populacional destas espécies, e aferir os efeitos da regulamentação da
apanha nos mananciais explorados. A abordagem conservacionista implícita ao longo desta tese
pretende promover: (i) a regulamentação adequada da apanha de caramujos (Phorcus sauciatus) e (ii)
a avaliação dos efeitos da regulamentação da apanha de lapas nas populações exploradas (Patella
aspera, Patella candei). Atualmente, os mananciais de lapas e caramujos são explorados perto do
rendimento máximo sustentável, e a monitorização e fiscalização são fundamentais para evitar a
futura sobre-exploração. A regulamentação da apanha de lapas produziu um efeito positivo nas
espécies de lapas exploradas, com um aumento no tamanho, na proporção de indivíduos
reprodutores, no tamanho de maturação e num maior equilíbrio na proporção de sexos. A apanha de
caramujos não está regulamentada e com o atual nível de exploração ocorrem alterações na estrutura
de tamanhos, abundância e potencial reprodutivo das populações exploradas, pelo que urge
implementar a regulamentação da apanha desta espécie, por forma a mitigar os efeitos negativos
desta atividade. O efeito da proximidade das populações humanas e acessibilidade costeira na
estrutura de tamanhos e abundância de gastrópodes explorados mostrou que a proporção de
reprodutores e a abundância eram geralmente menores em áreas mais próximas das populações
humanas e em áreas mais acessíveis. Os efeitos das Áreas Marinhas Protegidas na proteção das
populações de lapas resultaram num aumento diferencial do tamanho, da maturidade sexual e da
captura por unidade de esforço de acordo com o grau de proteção. O esclarecimento e envolvimento
das comunidades locais, reguladores, decisores políticos e partes interessadas, baseados em
informação e educação, são cruciais para uma gestão eficaz e sustentável destes gastrópodes marinhos
e ecossistemas a médio e longo prazo.Limpets and topshells are among the most successful intertidal grazers in the North-eastern Atlantic. These keystone species play a pivotal role in structuring rocky shores communities, and provoding valuable ecosystem services. Than have an important economic value, being subject to high levels of exploitation and representing one of the most profitable economic activities in small-scale fisheries in the archipelago of Madeira. This thesis aims to fill the gaps on the life-traits and population dynamics of these species, and assess the effects of harvesting regulations on the exploited stocks. A focus on conservation is implicit throughout this thesis since it addresses the promotion of: (i) proper regulation of the unregulated harvesting of topshells (Phorcus sauciatus) and (ii) provide additional information on the effects of harvesting regulations on limpets (Patella aspera, Patella candei). Currently, limpets and topshells stocks are being exploited near the maximum sustainable yield and monitoring and enforcement must be accomplished to avoid future overexploitation. Conservation measures prompted a positive effect on both exploited limpet species with an increase in length, reproductive individuals, size-at-first maturity and a more balanced sex-ratio after harvesting regulations. The harvesting of topshells is not regulated and with the current level of exploitation there are changes in the size structure, abundance and reproductive potential of the exploited populations, so it is imperative to implement the harvesting regulations for this species, in order to mitigate the negative effects of harvesting. The effect of proximity to human settlements and coastal accessibility on the size-structure and abundance of exploited gastropods showed that the mean-size, proportion of reproductive individuals and abundance were generally smaller in areas closer to human settlements and in more accessible areas. The effects of protection from the Marine Protected Areas on limpet populations resulted in a differential increase on size, size-at-first maturity and catch-per-unit-effort according to the degree of protection. The understanding and commitment of local communities, regulators, policymakers and stakeholders, based on information and education are crucial to the effective management and to ensure the sustainability of these marine gastropods and ecosystems at medium and long term.
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Matos, Ana Cristina Lemos de. "Insights into the European rabbit imune system: evolutionary history, diversity and expression of genes playing key roles in Myxoma vírus infection and host-resistence." Doctoral thesis, 2014. https://repositorio-aberto.up.pt/handle/10216/72074.
Full text
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Matos, Ana Cristina Lemos de. "Insights into the European rabbit imune system: evolutionary history, diversity and expression of genes playing key roles in Myxoma vírus infection and host-resistence." Tese, 2014. https://repositorio-aberto.up.pt/handle/10216/72074.
Full text
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McCaffrey, Anthony J. "The Obscure Features Hypothesis for innovation: One key to improving performance in insight problems." 2012. https://scholarworks.umass.edu/dissertations/AAI3518388.
Full textAbstract:
A new cognitive theory of innovation, the Obscure Features Hypothesis (OFH), states that many innovative solutions result from two steps: (1) noticing a rarely noticed or never-before noticed (i.e., obscure) feature of the problem's elements, and (2) then building a solution based on that obscure feature. The OFH deepens the analysis of the previous theories of innovation and opens up a systematic research program of uncovering aspects of the human semantic, perceptual, and motor systems that inhibit the noticing of obscure features and the derivation of counteracting techniques to unearth obscure features that have a high probability of being useful in problem solving. Specifically, in this study we derive a technique called the Generic Parts Technique (GPT) designed to unearth the types of obscure physical features that can counteract functional fixedness (Duncker, 1945) in insight problems involving concrete objects. Subjects trained in the GPT solved on average 33% more problems more than a control group, which has a very large standardized effect size, a Cohen's d of 1.6. Further, in a subsequent feature-listing task with concrete objects, the GPT subjects listed more obscure physical features. These results support the OFH in that obscure features seem to be one key to solving concrete object insight problems and techniques such as the GPT that are designed to unearth obscure features improve performance on these types of problems.