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Transcriptional Regulation By A Biotin Starvation- And Methanol-Inducible Zinc Finger Protein In The Methylotrophic Yeast, Pichia PastorisNallani, Vijay Kumar 11 1900 (has links) (PDF)
Pichia pastoris, a methylotrophic yeast is widely used for recombinant protein production. It has a well characterized methanol utilization (MUT) pathway, the enzymes of which are induced when cells are cultured in the presence of methanol. In this study, we have identified an unannotated zinc finger protein, which was subsequently named ROP (repressor of phosphoenolpyruvate carboxykinase, PEPCK) and characterized its function. ROP expression is induced in P. pastoris cells cultured in biotin depleted glucose ammonium medium as well as a medium containing methanol as the sole source of carbon. In glucose-abundant, biotin depleted cultures, ROP induces the expression of a number of genes including that encoding PEPCK. Interestingly, a strain in which the gene encoding ROP is deleted (ΔROP) exhibits biotin-independent growth. Based on a number of studies, it was proposed that the ability of ΔROP to grow in the absence of biotin is due to the activation of a pyruvate carboxylase-independent pathway of oxaloacetate biosynthesis. It was also proposed that PEPCK, which normally functions as a gluconeogenic enzyme, may act as an anaplerotic enzyme involved in the synthesis of oxaloacetate.
ROP was shown to be a key regulator of methanol metabolism when P. pastoris cells are cultured in YPM medium containing yeast extract, peptone and methanol but not YNBM medium containing yeast nitrogen base and methanol. In P. pastoris cells cultured in YPM, ROP functions as a transcriptional repressor of genes encoding key enzymes of the methanol metabolism such as the alcohol oxidase I. (AOXI). Deletion of the gene encoding ROP results in enhanced expression of AOXI and growth promotion while overexpression of ROP results in repression of AOXI and retardation of growth of P. pastoris cultured in YPM medium. Subcellular localization studies indicate that ROP translocates from cytosol to nucleus in cells cultured in YPM but not YNBM.
To understand the mechanism of action of ROP, we examined its DNA-binding specificity. The DNA-binding domain of ROP shares 57% amino acid identity with that of Mxr1p, a master regulator of genes of methanol metabolism. We demonstrate that the DNA-binding specificity of ROP is similar to that of Mxr1p and both proteins compete with each other for binding to AOXI promoter sequences. Thus, transcriptional interference due to competition between Mxr1p and ROP for binding to the same promoter sequences is likely to be the mechanism by which ROP represses AOXI expression in vivo. Mxr1p and ROP are examples of transcription factors which exhibit the same DNA-binding specificity but regulate gene expression in an antagonistic fashion.
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Podnikatelský plán rozvoje společnosti Golf Hrádek, s.r.o. / Business plan of following development of Golf Hrádek, s.r.o.Makovský, Petr January 2009 (has links)
The aim of diploma thesis is to evaluate the position of a small company offering services in a golf courses market. Following aims are to show reference both in short run investments and strategic investments. The main tools used in the document are the Porter's five forces, the SWOT analysis, and the analysis of criterions matrix. The output of the diploma statement is that the small company is strongly fixed in the market of golf services. The short term strategic recomendation is to focus on the needs of the target market customers as well as to increase the quality of the services and the golf environment. The main long term strategic recomendation is to rebuilt the old devastated building near by chateau Hrádek u Nechanic into a hotel and restaurant belonging to the golf course. This reconstruction needs to be funded with EU grants at least by 27% of the total cost, therefore by 30.922.000,- CZK.
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Algoritmy pro dopřední a zpětné plánování / Algorithms for forward and backward planningSluka, Filip January 2019 (has links)
The thesis deals with production planning. It contains theoretical description of methods used for production planning and optimizing. Thesis describes bottleneck problems in production. It offers overview of ways to identify and analyze bottleneck influence to manufacturing process efficiency. Thesis proposes ways to eliminate bottlenecks using various algorithm types. It applies theoretical knowledges from optimization and graph theory to program creation that is focused on order delay and readjustment time minimizing. The program implements genetic algorithm.
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The role of COCO in ocular angiogenesisPopovic, Natalija 04 1900 (has links)
Contexte: La néovascularisation pathologique oculaire entraîne plusieurs troubles de la cécité, y
compris la dégénérescence maculaire néovasculaire liée à l'âge (nDMLA) et la rétinopathie de la
prématurité (ROP). La nDMLA est la principale cause de cécité dans le monde industrialisé avec
un impact socio-économique considérable (1-6). Les thérapies palliatives actuelles reposent sur
la suppression du facteur de croissance de l'endothélium vasculaire (VEGF), prouvé sûr et efficace
(7-19). Cependant, certains patients résistent aux injections intravitréennes mensuelles répétées
d'anti-VEGF, et les conséquences à long terme comprennent une perte de vision supplémentaire
et une atrophie géographique (10, 14, 17, 18, 20-27). Cliniquement, il existe un besoin de
nouvelles cibles combinatoires ou alternatives dans les cliniques, permettant de réduire les doses
d'anti-VEGF, de traiter et d'étendre un intervalle approprié personnalisé à chaque patient non
répondeur, et de minimiser la charge des injections répétées (24, 25, 28, 29).
La famille TGF-β et sa sous-famille BMP sont cruciales dans l'angiogenèse oculaire physiologique
dans un modèle de ROP, et pourraient être des cibles thérapeutiques potentielles chez les
patients souffrant d’une nDMLA (30-66).
Hypothèse: COCO, un membre de la famille DAN, un modulateur connu des voies BMP et TGF-β,
agit comme un facteur neurotrophique sur les progéniteurs de photorécepteurs humains en
culture. Nous émettons l'hypothèse que les effets neurotrophiques et anti-angiogéniques de
COCO pourraient être des approches thérapeutiques bénéfiques pour empêcher la
néovascularisation dans la nDMLA ou la ROP.
Objectifs:
Objectif 1: Pour évaluer le rôle du COCO sur les maladies oculaires néovasculaires, nous
proposons d'étudier ses effets sur la néovascularisation rétinienne et choroïdienne dans le
développement et des modèles pathologiques de la DMLA et de la ROP lors d'injections
intravitréennes.
Objectif 2: Pour comprendre le rôle physiologique et le mécanisme d'action du COCO, nous
évaluerons les effets de COCO endogène au cours de l'angiogenèse et du développement
vasculaire oculaire.
Conclusions: Nous avons découvert un nouvel inhibiteur de l'angiogenèse, COCO, un membre de
la famille des protéines DAN. COCO abroge la migration et la prolifération des cellules
endothéliales de la veine ombilicale humaine, en partie grâce à sa régulation des voies TGF-β et
BMP et à une modification du métabolisme cellulaire et des gènes mitochondriaux.
Les injections intravitréennes de COCO suppriment la vascularisation rétinienne en cours du
développement et dans un modèle expérimental de ROP. COCO inhibe de la même manière la
néovascularisation choroïdienne dans un modèle de DMLA. De plus, COCO empêche
l'angiogenèse rétinienne développementale sans affecter le système vasculaire mature.
L'examen des souris Dand5 (COCO) KO a également montré un phénotype de développement
rétinien léger à P12 ainsi qu'une exacerbation des touffes néovasculaires dans un modèle de
rétinopathie induite par l'oxygène.
Impact: Nos données montrent que COCO inhibe la néovascularisation rétinienne et
choroïdienne et pourrait être une nouvelle thérapie possible pour des maladies oculaires. Nos
études fournissent des données sur les impacts de COCO sur le développement vasculaire
rétinien, établissent ses caractéristiques moléculaires et déterminent son importance biologique. / Background: Ocular pathological neovascularization leads to several blinding disorders, including
neovascular age‐related macular degeneration (nAMD) and retinopathy of prematurity (ROP).
nAMD, for instance, is the primary cause of blindness in the industrialized world with a
tremendous socioeconomic impact (1-6). Current palliative therapies rely on suppressing
vascular endothelial growth factor (VEGF), proven safe and effective (7-19). However, some
patients are resistant to monthly repeated intravitreal injections of anti-VEGF, and long-term
consequences comprise further vision loss and geographic atrophy (10, 14, 17, 18, 20-27).
Clinically, there is a necessity for novel combinatory or synergistic therapeutic targets to reduce
anti-VEGF treatment adherence. Novel personalized therapies to each non-responder patient
may increase efficiency while minimizing the burden of repeated injections (24, 25, 28, 29). The
TGF-β family, specifically the BMPs subfamily of proteins, is crucial in pathological ocular
angiogenesis in a model of pre-retinal neovascularization. These alternative pathways could be
potential therapeutic targets in nAMD patients as well (30-66).
Hypothesis: COCO, a member of the DAN family, is a known modulator of BMP and TGF-β
pathways and acts as a neurotrophic factor on cultured human photoreceptor progenitors. We
hypothesize that COCO’s neurotrophic and anti-angiogenic effects could exert therapeutic
benefits to preclude neovascularization in nAMD or ROP.
Objectives:
Aim 1: To assess the role of COCO on neovascular ocular diseases, we propose investigating its
effects on retinal and choroidal neovascularization in the development and pathological models
of AMD and ROP upon intravitreal injections.
Aim 2: To understand COCO's physiological role and mechanism of action, we evaluate the
exogenous and endogenous effects of COCO during angiogenesis and ocular vascular
development.
Conclusions: We discovered a novel inhibitor of angiogenesis, COCO, a DAN protein family
member. COCO abrogated sprouting migration and cellular proliferation of human umbilical vein
endothelial cells, partly through its regulation of TGF-β and BMP pathways and cellular
metabolism.
Intravitreal injections of COCO suppress retinal vascularization in development and an
experimental model of ROP. COCO similarly inhibits choroidal neovascularization in an nAMD
model. COCO prevents developmental retinal angiogenesis without affecting the mature
vasculature. Examination of Dand5 (COCO) KO mice also shows a mild retinal developmental
phenotype at P12 as well as an exacerbation of neovascular tufts in a model of oxygen-induced
retinopathy.
Impact: Our data show that COCO inhibits retinal and choroidal neovascularization and could be
of potential therapeutic use in treating neovascular ocular diseases. Our studies set grounds for
understanding the role of COCO during retinal vascular development, characterizing its molecular
features, and determining its biologic significance.
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Understanding Relational Agility: Exploring Constructs of Relational Leadership Through StoryMcLean, David M.I. 10 April 2014 (has links)
No description available.
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On the (in)security of behavioral-based dynamic anti-malware techniquesErsan, Erkan 21 April 2017 (has links)
The Internet has become the primary vector for the delivery of malicious code in cyber attacks, and malware has rapidly become a pervasive critical threat. Anti- malware products offer effective protection from malware threats for servers and endpoint devices using a variety of techniques. Advanced enterprise-level anti-malware products rely on state-of-art behavioral-based detection algorithms, in addition to traditional signature-based mechanisms. These dynamic detection techniques have been around for more than a decade and in response hackers have developed methods to evade them. However, currently known bypass methods require intensive manual labor. Moreover, this manual work has to be repeated whenever a parameter of the environment (such as the payload, operating system, Antivirus version, etc) changes, making these methods impractical. This may lead to the belief that dynamic techniques provide a good deterrence, and hence good protection.
In this thesis we evaluate dynamic techniques. Specifically, we build tools to implement generic unhooking and funneling, and using these tools we show how dynamic techniques can be bypassed with considerably less effort than by fully manual methods. We also extend the repertoire of existing bypass methods and introduce a new malicious function call technique which exploits detection techniques that monitor a limited collection of critical system functions, as well as a method for bypassing guard-page protections. We demonstrate the effectiveness of all our techniques by conducting attacks against two enterprise antivirus products. Our results lead us to conclude that that dynamic techniques do not provide sufficient protection. / Graduate / 2018-02-07 / 0984 / erkanersan@gmail.com
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