Academic literature on the topic 'Biogenesis of replication compartments'
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Journal articles on the topic "Biogenesis of replication compartments"
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Ci, Yali, and Lei Shi. "Compartmentalized replication organelle of flavivirus at the ER and the factors involved." Cellular and Molecular Life Sciences 78, no. 11 (April 12, 2021): 4939–54. http://dx.doi.org/10.1007/s00018-021-03834-6.
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AbstractFlaviviruses are positive-sense single-stranded RNA viruses that pose a considerable threat to human health. Flaviviruses replicate in compartmentalized replication organelles derived from the host endoplasmic reticulum (ER). The characteristic architecture of flavivirus replication organelles includes invaginated vesicle packets and convoluted membrane structures. Multiple factors, including both viral proteins and host factors, contribute to the biogenesis of the flavivirus replication organelle. Several viral nonstructural (NS) proteins with membrane activity induce ER rearrangement to build replication compartments, and other NS proteins constitute the replication complexes (RC) in the compartments. Host protein and lipid factors facilitate the formation of replication organelles. The lipid membrane, proteins and viral RNA together form the functional compartmentalized replication organelle, in which the flaviviruses efficiently synthesize viral RNA. Here, we reviewed recent advances in understanding the structure and biogenesis of flavivirus replication organelles, and we further discuss the function of virus NS proteins and related host factors as well as their roles in building the replication organelle.
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Lin, Wenwu, Zhike Feng, K. Reddisiva Prasanth, Yuyan Liu, and Peter D. Nagy. "Dynamic interplay between the co-opted Fis1 mitochondrial fission protein and membrane contact site proteins in supporting tombusvirus replication." PLOS Pathogens 17, no. 3 (March 16, 2021): e1009423. http://dx.doi.org/10.1371/journal.ppat.1009423.
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Plus-stranded RNA viruses have limited coding capacity and have to co-opt numerous pro-viral host factors to support their replication. Many of the co-opted host factors support the biogenesis of the viral replication compartments and the formation of viral replicase complexes on subverted subcellular membrane surfaces. Tomato bushy stunt virus (TBSV) exploits peroxisomal membranes, whereas the closely-related carnation Italian ringspot virus (CIRV) hijacks the outer membranes of mitochondria. How these organellar membranes can be recruited into pro-viral roles is not completely understood. Here, we show that the highly conserved Fis1 mitochondrial fission protein is co-opted by both TBSV and CIRV via direct interactions with the p33/p36 replication proteins. Deletion ofFIS1in yeast or knockdown of the homologous Fis1 in plants inhibits tombusvirus replication. Instead of the canonical function in mitochondrial fission and peroxisome division, the tethering function of Fis1 is exploited by tombusviruses to facilitate the subversion of membrane contact site (MCS) proteins and peroxisomal/mitochondrial membranes for the biogenesis of the replication compartment. We propose that the dynamic interactions of Fis1 with MCS proteins, such as the ER resident VAP tethering proteins, Sac1 PI4P phosphatase and the cytosolic OSBP-like oxysterol-binding proteins, promote the formation and facilitate the stabilization of virus-induced vMCSs, which enrich sterols within the replication compartment. We show that this novel function of Fis1 is exploited by tombusviruses to build nuclease-insensitive viral replication compartment.
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Nagy, Peter D. "Exploitation of Host Factors and Cellular Pathways by Tombusviruses for the Biogenesis of the Viral Replication Organelles." Proceedings 50, no. 1 (June 4, 2020): 18. http://dx.doi.org/10.3390/proceedings2020050018.
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Plus-stranded RNA viruses recruit cellular vesicles and co-opt cellular proteins involved in cellular metabolism and lipid biosynthesis to build viral replicase complexes (VRCs) within the large viral replication compartments. We use tombusviruses (TBSV), which are small (+)RNA viruses, as model plant viruses to study virus replication, recombination, and virus–host interactions using yeast (Saccharomyces cerevisiae) as a surrogate host. Several systematic genome-wide screens and global proteomic and lipidomic approaches have led to the identification of ~500 host proteins/genes that are implicated in TBSV replication. We characterized the role of two-dozen co-opted host proteins, sterols, and phosphatidylethanolamine in tombusvirus VRC assembly and viral RNA synthesis. We provide evidence on the critical roles of phosphoinositides and co-opted membrane-shaping proteins in VRC formation. We also present data that tombusviruses hijack the glycolytic and fermentation pathways to obtain ATP, which is required for the biogenesis of the replication compartment. Finally, we show evidence that TBSV usurps COPII and endosomal vesicles to form a unique microenvironment involving peroxisomes and endoplasmic reticulum (ER) to support viral replication. These new insights highlight the amazingly complex nature of virus-host interactions.
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Ortiz, Cristina Risco. "Imaging Viral Factories." Proceedings 50, no. 1 (June 1, 2020): 3. http://dx.doi.org/10.3390/proceedings2020050003.
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Viruses remodel cellular compartments to build their replication factories. Remarkably, viruses are also able to induce new membranes and new organelles. As a result of recent advances in light and transmission electron microscopy (TEM), we are starting to become aware of the variety of structures that viruses assemble inside cells. Viral factories are intracellular compartments harboring replication organelles that contain viral replication complexes and the sites of virus particle assembly. This lecture will revise the most relevant imaging technologies for studying the biogenesis of viral replication factories. Live cell microscopy, correlative light and electron microscopy, cryo-TEM, and three-dimensional imaging methods are unveiling how viruses manipulate cell organization. In particular, methods for molecular mapping in situ, in two and three dimensions, are revealing how macromolecular complexes build functional replication complexes inside infected cells. The combination of all these imaging approaches is uncovering the viral lifecycle events with a detail never seen before.
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Reuter, Tatjana, Stephanie Vorwerk, Viktoria Liss, Tzu-Chiao Chao, Michael Hensel, and Nicole Hansmeier. "Proteomic Analysis of Salmonella-modified Membranes Reveals Adaptations to Macrophage Hosts." Molecular & Cellular Proteomics 19, no. 5 (February 26, 2020): 900–912. http://dx.doi.org/10.1074/mcp.ra119.001841.
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Systemic infection and proliferation of intracellular pathogens require the biogenesis of a growth-stimulating compartment. The gastrointestinal pathogen Salmonella enterica commonly forms highly dynamic and extensive tubular membrane compartments built from Salmonella-modified membranes (SMMs) in diverse host cells. Although the general mechanism involved in the formation of replication-permissive compartments of S. enterica is well researched, much less is known regarding specific adaptations to different host cell types. Using an affinity-based proteome approach, we explored the composition of SMMs in murine macrophages. The systematic characterization provides a broader landscape of host players to the maturation of Salmonella-containing compartments and reveals core host elements targeted by Salmonella in macrophages as well as epithelial cells. However, we also identified subtle host specific adaptations. Some of these observations, such as the differential involvement of the COPII system, Rab GTPases 2A, 8B, 11 and ER transport proteins Sec61 and Sec22B may explain cell line-dependent variations in the pathophysiology of Salmonella infections. In summary, our system-wide approach demonstrates a hitherto underappreciated impact of the host cell type in the formation of intracellular compartments by Salmonella.
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Arakawa, Masashi, and Eiji Morita. "Flavivirus Replication Organelle Biogenesis in the Endoplasmic Reticulum: Comparison with Other Single-Stranded Positive-Sense RNA Viruses." International Journal of Molecular Sciences 20, no. 9 (May 11, 2019): 2336. http://dx.doi.org/10.3390/ijms20092336.
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Some single-stranded positive-sense RNA [ssRNA(+)] viruses, including Flavivirus, generate specific organelle-like structures in the host endoplasmic reticulum (ER). These structures are called virus replication organelles and consist of two distinct subdomains, the vesicle packets (VPs) and the convoluted membranes (CMs). The VPs are clusters of small vesicle compartments and are considered to be the site of viral genome replication. The CMs are electron-dense amorphous structures observed in proximity to the VPs, but the exact roles of CMs are mostly unknown. Several recent studies have revealed that flaviviruses recruit several host factors that are usually used for the biogenesis of other conventional organelles and usurp their function to generate virus replication organelles. In the current review, we summarize recent studies focusing on the role of host factors in the formation of virus replication organelles and discuss how these intricate membrane structures are organized.
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Dolnik, Olga, Gesche K. Gerresheim, and Nadine Biedenkopf. "New Perspectives on the Biogenesis of Viral Inclusion Bodies in Negative-Sense RNA Virus Infections." Cells 10, no. 6 (June 10, 2021): 1460. http://dx.doi.org/10.3390/cells10061460.
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Infections by negative strand RNA viruses (NSVs) induce the formation of viral inclusion bodies (IBs) in the host cell that segregate viral as well as cellular proteins to enable efficient viral replication. The induction of those membrane-less viral compartments leads inevitably to structural remodeling of the cellular architecture. Recent studies suggested that viral IBs have properties of biomolecular condensates (or liquid organelles), as have previously been shown for other membrane-less cellular compartments like stress granules or P-bodies. Biomolecular condensates are highly dynamic structures formed by liquid-liquid phase separation (LLPS). Key drivers for LLPS in cells are multivalent protein:protein and protein:RNA interactions leading to specialized areas in the cell that recruit molecules with similar properties, while other non-similar molecules are excluded. These typical features of cellular biomolecular condensates are also a common characteristic in the biogenesis of viral inclusion bodies. Viral IBs are predominantly induced by the expression of the viral nucleoprotein (N, NP) and phosphoprotein (P); both are characterized by a special protein architecture containing multiple disordered regions and RNA-binding domains that contribute to different protein functions. P keeps N soluble after expression to allow a concerted binding of N to the viral RNA. This results in the encapsidation of the viral genome by N, while P acts additionally as a cofactor for the viral polymerase, enabling viral transcription and replication. Here, we will review the formation and function of those viral inclusion bodies upon infection with NSVs with respect to their nature as biomolecular condensates.
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Hardiman, Camille A., Justin A. McDonough, Hayley J. Newton, and Craig R. Roy. "The role of Rab GTPases in the transport of vacuoles containing Legionella pneumophila and Coxiella burnetii." Biochemical Society Transactions 40, no. 6 (November 21, 2012): 1353–59. http://dx.doi.org/10.1042/bst20120167.
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Intracellular pathogens survive in eukaryotic cells by evading a variety of host defences. To avoid degradation through the endocytic pathway, intracellular bacteria must adapt their phagosomes into protective compartments that promote bacterial replication. Legionella pneumophila and Coxiella burnetii are Gram-negative intracellular pathogens that remodel their phagosomes by co-opting components of the host cell, including Rab GTPases. L. pneumophila and C. burnetii are related phylogenetically and share an analogous type IV secretion system for delivering bacterial effectors into the host cell. Some of these effectors mimic eukaryotic biochemical activities to recruit and modify Rabs at the vacuole. In the present review, we cover how these bacterial species, which utilize divergent strategies to establish replicative vacuoles, use translocated proteins to manipulate host Rabs, as well as exploring which Rabs are implicated in vacuolar biogenesis in these two organisms.
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Iarovaia, Olga V., Elena S. Ioudinkova, Artem K. Velichko, and Sergey V. Razin. "Manipulation of Cellular Processes via Nucleolus Hijaking in the Course of Viral Infection in Mammals." Cells 10, no. 7 (June 25, 2021): 1597. http://dx.doi.org/10.3390/cells10071597.
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Due to their exceptional simplicity of organization, viruses rely on the resources, molecular mechanisms, macromolecular complexes, regulatory pathways, and functional compartments of the host cell for an effective infection process. The nucleolus plays an important role in the process of interaction between the virus and the infected cell. The interactions of viral proteins and nucleic acids with the nucleolus during the infection process are universal phenomena and have been described for almost all taxonomic groups. During infection, proteins of the nucleolus in association with viral components can be directly used for the processes of replication and transcription of viral nucleic acids and the assembly and transport of viral particles. In the course of a viral infection, the usurpation of the nucleolus functions occurs and the usurpation is accompanied by profound changes in ribosome biogenesis. Recent studies have demonstrated that the nucleolus is a multifunctional and dynamic compartment. In addition to the biogenesis of ribosomes, it is involved in regulating the cell cycle and apoptosis, responding to cellular stress, repairing DNA, and transcribing RNA polymerase II-dependent genes. A viral infection can be accompanied by targeted transport of viral proteins to the nucleolus, massive release of resident proteins of the nucleolus into the nucleoplasm and cytoplasm, the movement of non-nucleolar proteins into the nucleolar compartment, and the temporary localization of viral nucleic acids in the nucleolus. The interaction of viral and nucleolar proteins interferes with canonical and non-canonical functions of the nucleolus and results in a change in the physiology of the host cell: cell cycle arrest, intensification or arrest of ribosome biogenesis, induction or inhibition of apoptosis, and the modification of signaling cascades involved in the stress response. The nucleolus is, therefore, an important target during viral infection. In this review, we discuss the functional impact of viral proteins and nucleic acid interaction with the nucleolus during infection.
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Kujala, Pekka, Anne Ikäheimonen, Neda Ehsani, Helena Vihinen, Petri Auvinen, and Leevi Kääriäinen. "Biogenesis of the Semliki Forest Virus RNA Replication Complex." Journal of Virology 75, no. 8 (April 15, 2001): 3873–84. http://dx.doi.org/10.1128/jvi.75.8.3873-3884.2001.
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ABSTRACT The nonstructural (ns) proteins nsP1 to -4, the components of Semliki Forest virus (SFV) RNA polymerase, were localized in infected cells by confocal microscopy using double labeling with specific antisera against the individual ns proteins. All ns proteins were associated with large cytoplasmic vacuoles (CPV), the inner surfaces of which were covered by small invaginations, or spherules, typical of alphavirus infection. All ns proteins were localized by immuno-electron microscopy (EM) to the limiting membranes of CPV and to the spherules, together with newly labeled viral RNA. Along with earlier observations by EM-autoradiography (P. M. Grimley, I. K. Berezesky, and R. M. Friedman, J. Virol. 2:326–338, 1968), these results suggest that individual spherules represent template-associated RNA polymerase complexes. Immunoprecipitation of radiolabeled ns proteins showed that each antiserum precipitated the other three ns proteins, implying that they functioned as a complex. Double labeling with organelle-specific and anti-ns-protein antisera showed that CPV were derivatives of late endosomes and lysosomes. Indeed, CPV frequently contained endocytosed bovine serum albumin-coated gold particles, introduced into the medium at different times after infection. With time, increasing numbers of spherules were also observed on the cell surfaces; they were occasionally released into the medium, probably by secretory lysosomes. We suggest that the spherules arise by primary assembly of the RNA replication complexes at the plasma membrane, guided there by nsP1, which has affinity to lipids specific for the cytoplasmic leaflet of the plasma membrane. Endosomal recycling and fusion of CPV with the plasma membrane can circulate spherules between the plasma membrane and the endosomal-lysosomal compartment.
Dissertations / Theses on the topic "Biogenesis of replication compartments"
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Bakhache, William. "Interactions de la protéine nsP1 du virus Chikungunya avec les membranes de l’hôte et conséquences fonctionnelles." Thesis, Montpellier, 2020. http://www.theses.fr/2020MONTT008.
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Les virus à ARN de polarité positive (ARN(+)) partagent la capacité de réorganiser les membranes cellulaires en organelles vésiculaires. Ces compartiments, appelés organelles de réplication (OR), fournissent un environnement approprié permettant d’héberger la machinerie de réplication virale, ses cofacteurs cellulaires et les ARN viraux néo-synthétisés. En raison de leur rôle indispensable à la réplication virale, ces compartiments et les mécanismes moléculaires nécessaires à leur assemblage ont suscité un réel intérêt ces dernières années. Alors que des progrès significatifs ont été réalisés dans ce domaine pour d’autres virus à ARN(+), peu de données relatives au mécanisme de formation des ORs des Alphavirus ont été produites. Ces virus ont pourtant été associés à des enjeux majeurs de santé publique au cours de la dernière décennie, en particulier avec la propagation récente du virus Chikungunya (CHIKV). CHIKV est en effet un virus réémergent transmis par les moustiques et à l’origine d’épidémies ayant des conséquences socio-économiques dévastatrices dans les pays où il se propage. Les symptômes se caractérisent par une forte fièvre et une éruption cutanée, avec un pourcentage significatif de patients qui souffrent de douleurs articulaires à long terme, souvent invalidantes. À l’heure actuelle, il n’existe aucun vaccin ou traitement antiviral pour ce virus.Les OR de CHIKV se présentent comme des sphérules de 50 à 60 nm résultant d’une courbure négative de la membrane plasmique. À l’intérieur de ces compartiments, la machinerie de réplication est ancrée à la membrane par l’interaction directe de la protéine non structurale 1 (nsP1) avec la bicouche lipidique. Cette protéine virale, exprimée de façon isolée, conduit à des déformations membranaires de type filopodes. Ainsi, nsP1 apparait comme un acteur majeur du remodelage membranaire au cours de l’infection par les Alphavirus. Dans ce contexte, le but de cette thèse, centrée sur nsP1, est de caractériser les interactions de nsP1 avec les membranes cellulaires et de définir les conséquences fonctionnelles de ces interactions dans la réplication virale. Nous avons mis en évidence le rôle du métabolisme lipidique dans l’ancrage membranaire de nsP1 et dans l’infection virale. Nos résultats indiquent que la production d’acides gras est nécessaire au cycle infectieux et favorise l’interaction de nsP1 avec les membranes. Ils mettent en évidence le rôle complètement nouveau des acides gras insaturés dans l’étape de réplication des Alphavirus. Nous avons également démontré l’affinité de la forme palmitoylée de nsP1 pour les microdomaines lipidiques riches en cholestérol de la membrane plasmique. Nous avons établi les conséquences fonctionnelles de cette affinité sur la localisation des autres protéines non structurales et sur la réplication virale. Enfin, nous avons défini l’interactome fonctionnel de nsP1, de façon à identifier les cofacteurs cellulaires pouvant contribuer aux déformations membranaires induites par cette protéine virale. Ce travail permet de mieux comprendre les mécanismes de déformation membranaires observés au cours de l’infection par les AlphavirusPositive strand RNA ((+) RNA) viruses share the common capacity to rearrange cellular membranes into vesicular organelles. These membranous compartments referred to as replication organelles (ROs), are seen as providing an appropriate environment recruiting all viral components and cofactors required for replication. Because of their strict necessity for viral replication, these compartments and the molecular mechanisms required for their assembly have generated an intense interest in recent years. Contrasting with the consequential advances made in this field for other (+)RNA viruses, virtually no mechanistic data has been produced on the formation of ROs by Alphaviruses which in the last decade have proven to be medically paramount viruses, especially with the recent spread of Chikungunya virus (CHIKV). CHIKV is a re-emerging virus transmitted by mosquitoes that has caused outbreaks with devastating socio-economic impact in countries where it propagates. Symptoms include high fever and rash, with a significant percentage of patients suffering of long-term, often incapacitating, joint pain. Currently there is no vaccine or anti-viral treatment for this virus.CHIKV ROs appear as 50-60 nm electron translucent bulb-shaped spherules resulting from negative curvature at the plasma membrane. Inside these compartments, the replication machinery is anchored to the membrane through the direct interaction of the non-structural protein 1 (nsP1) with the lipid bilayer. When expressed as an isolated protein nsP1 dramatically remodels cellular membranes into filopodia-like protrusions. Therefore, this designated nsP1 as a critical factor in cellular membrane reshaping observed during infection. In this context, the aim of this thesis, with nsP1 at its centerpiece, is to characterize nsP1 interactions with cellular membranes and to define their functional consequences on viral replication. In this investigation, we have demonstrated the role of host cell lipid metabolism in nsP1 membrane anchoring and viral infection. Our results indicate that fatty acid synthesis is required for viral life cycle and favors nsP1 interaction with membranes. We also provide the very first information on the role of unsaturated fatty acids in Alphavirus replication. In-depth studies on the role of cholesterol revealed that palmitoylated nsP1 anchored CHIKV non-structural proteins to cholesterol-rich microdomains with functional consequences on replication. Finally, we have identified nsP1 interactome in order to identify host-cofactors required for the membrane deformation induced by this viral protein. Taken together, this thesis provides new information on nsP1/membrane lipids and host cofactors interplay. This work will allow the further comprehension of the mechanisms behind membrane deformation observed during Alphavirus replication
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Gokay, Kerimi Erden. "Morphology and biogenesis of endosomal compartments in epithelial cells." Diss., The University of Arizona, 2000. http://hdl.handle.net/10150/279796.
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Epithelial tissues which line the body cavities and tubules typically face two environments that are biochemically and physically different from each other. Consequently, these cells possess two structurally and functionally distinct plasma membrane domains; an apical domain facing the lumenal or the free surface and a basolateral domain facing the basement membrane and the intercellular space. Furthermore, via processes such as domain selective absorption, secretion and transcytosis, epithelial cells not only maintain these trans-epithelial differences but also actively contribute to their generation. Therefore, maintenance of high fidelity in polarized protein sorting and membrane trafficking aee of cardinal importance in all epithelia for their proper function. Although the central role membrane trafficking plays in generation and maintenance of epithelial cell polarity is clear, nature of the endosomal compartment(s) involved and the molecular determinants employed in this process remains ill-defined. In this study, using a unique apical endosomal marker, endotubin, and a model polarized epithelial cell line, Madin-Darby canine kidney (MDCK), we characterize the endotubin-positive endosomes as a subset of apical early endosomes which can be reached with an endocytic marker only when it is internalized apically. Furthermore, we show that endotubin-positive endosomes do not contain basolaterally recycling transferrin or the small GTPase Rab 11 and therefore they are distinct from the previously described apical recycling endosomes (ARE) in MDCK cells. In addition, using a panel of endotubin mutants we characterize two cytoplasmic sorting signals, a hydrophobic cluster and a casein kinase II phosphorylation site, as the molecular determinants required for polarized sorting and endosomal targeting of this molecule. Also, using a panel of domain exchange chimeras we show that endotubin cytoplasmic domain is sufficient to mediate apical sorting and early endosomal targeting of an unrelated protein in MDCK cells. Nevertheless, overexpression of these chimeras but not a mutant form defective in endosomal targeting results in missorting of the construct to the basolateral domain. These results indicate that, the endotubin-positive apical endosomes possess a saturable sorting machinery capable of recognizing the cytoplasmic sorting determinants here we characterize.
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Carling, Phillippa Julia. "Mitochondrial DNA replication and biogenesis during embryonic development and in disease." Thesis, University of Newcastle upon Tyne, 2014. http://hdl.handle.net/10443/2633.
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Regulation of mtDNA content is critical to normal human health and is often abnormal in mitochondrial diseases. Only a proportion of a female’s mtDNA is used to populate the oocytes she forms during embryogenesis. This mtDNA bottleneck can cause rapid shifts in heteroplasmy levels between generations in families with mtDNA mutations. The heteroplasmy levels of several mtDNA mutations were analysed from mother-child pairs using previously validated pyrosequencing assays. Analysis of the shifts in heteroplasmy caused by the mtDNA bottleneck reveals that the inheritance of the pathogenic tRNA mutations m.3243A>G and m.8344A>G do not show selection bias. However, the distribution of m.8993T>G (in MT-ATP6) in offspring suggests this mutation is selected for during the mtDNA bottleneck. This finding is in agreement with meta-analysis performed on previously published data, which also reveals biased inheritance of the LHON mutations m.11778G>A and m.3460G>A, in Complex I genes. Selection for these mutations explains the higher prevalence of homoplasmy, as fixation can occur within fewer generations. Crucial to formation of the mtDNA bottleneck is the dramatic increase in mtDNA replication rate that allows primordial germ cells (PGCs) to repopulate their mitochondrial genomes. Gene expression analysis during pre-implantation embryonic development has not revealed any other biological processes associated with regulation of mtDNA copy number. Upregulation of Lrpprc correlates with the expression of transcription factors as pre-implantation development progresses at this stage. The limited number of PGCs in the early stages of post-implantation development prevented sufficient quantity of high-quality RNA to be isolated for use with gene expression analysis. The reduction of mtDNA copy number observed during the mtDNA bottleneck was modelled in myoblasts and fibroblasts, using ddC, a reverse transcriptase inhibitor. Although some gene expression changes were induced during repopulation of mtDNA, these were limited to below 3-fold change. Forcing reliance on oxidative phosphorylation through culture with galactose media could not increase the rate of mtDNA replication or induce greater gene expression responses. Ragged-red fibres (RRFs) are a common hallmark of many mitochondrial diseases, caused by proliferation of mitochondria in the subsarcolemmal region of muscle tissue. Multiplex immunohistochemistry allowed fibre typing and identification of RRFs in muscle tissue from a patient with the m.8344A>G mutation. A novel technique was iii established to ensure extraction of intact high-quality RNA from laser-microdissected muscle fibres. The RNA was used in a pilot microarray experiment to study the differences not only between control and patient tissue, but specifically within RRF, and has identified a multitude of potential signalling pathways involved in mitochondrial biogenesis and formation of RRFs. This thesis reveals the complexity of mtDNA copy number regulation and, the critical involvement it has to human health and the inheritance and pathogenicity of mitochondrial diseases.
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Kaspari, Marion. "Die Rolle des Proteasoms für die Replikation des humanen Cytomegalievirus." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2009. http://dx.doi.org/10.18452/16005.
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Das Humane Cytomegalievirus (HCMV) ist ein ubiquitäres Pathogen, welches den Metabolismus der Wirtszelle auf vielfältige Weise manipuliert, um seine eigene Vermehrung zu begünstigen. In der vorliegenden Arbeit konnte nachgewiesen werden, dass auch das Ubiquitin-Proteasom-System in die HCMV-Replikation involviert ist. So konnte zunächst gezeigt werden, dass die Chymotrypsin-ähnliche (CT-L) Aktivität des konstitutiven Proteasoms in HCMV-infizierten Zellen signifikant erhöht ist. Wurde die CT-L Proteasomaktivität durch Proteasominhibitoren (PI) blockiert, so hatte dies die Hemmung der HCMV-Replikation zur Folge. Die Charakterisierung des Einflusses von PI auf die virale Proteinexpression ergab, dass bei niedriger MOI (MOI 0.1) deutlich verringerte Mengen der sehr frühen Proteine vorlagen, dieser Effekt jedoch bei hoher MOI (ab MOI 1) aufgehoben war. Die Expression früher Proteine war MOI-unabhängig reduziert. Hingegen war die Expression der späten Proteine MOI-unabhängig vollständig unterdrückt. Studien mit dem Nukleosidanalogon BrdU ergaben zudem, dass die de novo Synthese viraler DNA blockiert war. Um erste Hinweise auf den Wirkungsmechanismus von PI zu erhalten, wurde untersucht, ob der Transkriptionsfaktor NF-kappaB oder zelluläre Transkriptionsrepressoren wie z.B. hDaxx am anti-HCMV-Effekt beteiligt sind. Durch die Charakterisierung einer Virusmutante mit Deletion der NF-kappaB-Bindestellen im MIE-Enhancer/Promotor konnte gezeigt werden, dass der antivirale Effekt von PI nicht auf der Hemmung der Aktivierung von NF-kappaB beruht. Experimente mit hDaxx-knockdown Zellen ergaben hingegen, dass die Stabilisierung des Transkriptionsrepressors hDaxx partiell zum anti-HCMV-Effekt von PI beiträgt. Darüber hinaus müssen jedoch weitere virale oder zelluläre Zielproteine existieren, deren Beeinflussung durch PI kritisch für die Virusreplikation ist. Zusammenfassend stellt das Proteasom somit einen neu identifizierten potentiellen Angriffspunkt für die anti-HCMV-Therapie dar.The Human Cytomegalovirus (HCMV) is a ubiquitous pathogen that manipulates many aspects of the host cell metabolism to enhance viral replication. This work demonstrates that the ubiquitin-proteasome system is also involved in HCMV replication. First of all, the chymotrypsin-like (CT-L) activity of the constitutive proteasome was significantly increased in HCMV infected cells. In the presence of proteasome inhibitors (PI) viral replication was efficiently blocked. Characterisation of the influence of PI on viral protein expression showed that immediate early protein expression was clearly reduced at low MOI (MOI 0.1); however, this effect was abolished at high MOI (starting from MOI 1). Expression of early proteins was significantly decreased independently of the MOI used for infection. In contrast, late protein expression was completely suppressed at both low and high MOI. Additionally, studies using the nucleoside analogue BrdU showed that PI block the de novo synthesis of viral DNA. In order to gain insight into the working mechanism of PI the involvement of the transcription factor NF-kappaB and cellular repressors of transcription (e.g. hDaxx) in the antiviral effect of PI was examined. Studies using a mutant virus carrying deletions of the NF-kappaB binding sites in the MIE-enhancer/promoter revealed that the anti-HCMV effect of PI is not due to inhibition of NF-kappaB activation. Analyses using hDaxx-knockdown cells showed that stabilisation of the transcriptional repressor hDaxx partially contributes to the antiviral effect of PI. However, the existence of additional viral or cellular target proteins of PI is very likely. In summary, the proteasome thus represents a newly identified and promising target for anti-HCMV therapy.
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"Biogenesis and turnover of prevacuolar compartments (PVCs) in Arabidopsis thaliana cells." 2011. http://library.cuhk.edu.hk/record=b5894503.
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Cui, Yong.Thesis (M.Phil.)--Chinese University of Hong Kong, 2011.
Includes bibliographical references (leaves 73-84).
Abstracts in English and Chinese.
Thesis/Assessment Committee --- p.ii
Statement --- p.iii
Acknowledgements --- p.iv
Abstract --- p.v
摘要 --- p.vi
Table of Contents --- p.vii
List of Figures --- p.xi
List of Supplemental Tables --- p.xiii
List of Abbreviations --- p.xiii
Chapter Chapter 1 --- General Introduction --- p.1
Chapter 1.1 --- The plant secretory and endocytosis pathways --- p.2
Chapter 1.2 --- Rab proteins --- p.4
Chapter 1.2.1 --- Overview of the small GTPases --- p.4
Chapter 1.2.2 --- Function of Rab proteins in Arabidopsis --- p.6
Chapter 1.3 --- Prevacuolar compartments --- p.9
Chapter 1.3.1 --- PVCs in mammalian and yeast cells --- p.9
Chapter 1.3.2 --- PVCs in plant cells --- p.9
Chapter 1.4 --- Vacuolar Sorting Receptors --- p.10
Chapter 1.5 --- Project objectives --- p.10
Chapter CHAPTER 2 --- Early and Late Prevacuolar Compartments in Arabidopsis thaliana Cells --- p.12
Chapter 2.1 --- Introduction --- p.13
Chapter 2.2 --- MATERIALS AND METHODS --- p.19
Chapter 2.2.1 --- Plasmid Construction --- p.19
Chapter 2.2.2 --- Plants materials and growth conditions --- p.19
Chapter 2.2.3 --- Transient Expression of Arabidopsis suspension cultured cells --- p.20
Chapter 2.2.4 --- Confocal imaging studies --- p.21
Chapter 2.3 --- RESULTS --- p.23
Chapter 2.3.1 --- Organelle markers serve as a tool to study biogenesis and turnover of PVCs --- p.23
Chapter 2.3.2 --- AtRab5 and AtRab7 proteins show distinct but closely associated patterns in the PVC-to-Vacuole pathway --- p.26
Chapter 2.3.3 --- AtRab5 and AtRab7 proteins localize on the distinct organellein Arabidopsis thaliana protoplasts --- p.32
Chapter 2.3.4 --- AtRab5 proteins are closely associated with AtRab7 proteins --- p.35
Chapter 2.3.5 --- ARA7-Q69L proteins recruit a SNARE complex onto the enlarged PVCs --- p.37
Chapter 2.4 --- Discussion --- p.40
Chapter 2.4.1 --- PVC dynamics in Arabidopsis cells --- p.40
Chapter 2.4.2 --- AtVSR and its point mutation form defined different stages of PVCs in Arabidopsis thaliana protoplasts --- p.41
Chapter 2.4.3 --- AtRab7 proteins localized on the tonoplast and newly defined late PVCs --- p.41
Chapter CHAPTER 3 --- AtRab7 proteins play a critical role in mediating vacuolar trafficking in Arabidopsis thaliana Cells --- p.43
Chapter 3.1 --- Introduction --- p.44
Chapter 3.2 --- MATERIALS AND METHODS --- p.45
Chapter 3.2.1 --- Plasmid Construction --- p.45
Chapter 3.2.2 --- Plants materials and growth conditions --- p.45
Chapter 3.2.3 --- Transient Expression of Arabidopsis suspension cultured cells --- p.45
Chapter 3.2.4 --- Confocal imaging studies --- p.45
Chapter 3.2.5 --- Drug treatment --- p.46
Chapter 3.3 --- RESULTS --- p.48
Chapter 3.3.1 --- Mutations at GTP-binding motifs and the effector domain affect the subcellular localization of AtRabG3e --- p.48
Chapter 3.3.2 --- "AtRabG3e-T22N induced vacuolation of YFP-ARA7 marked PVCs, which remains separated from ER, Golgi and TGN but colocalizes with early PVC markers" --- p.51
Chapter 3.3.3 --- AtRab7-T22N inhibits vacuolar trafficking of cargo proteins --- p.54
Chapter 3.3.4 --- Wortmannin-induced vacuolation of late PVCs in transgenic plants --- p.57
Chapter 3.4 --- Discussion --- p.59
Chapter 3.4.1 --- The proper targeting of AtRab7 proteins --- p.59
Chapter 3.4.2 --- AtRab5 and AtRab7 proteins are essential for vacuolar protein trafficking --- p.59
Chapter CHAPTER 4 --- Summary and Future Perspectives --- p.61
Chapter 4.1 --- Summary --- p.62
Chapter 4.1.1 --- Localization of AtRab5 and AtRab7 proteins on different populations of PVCs --- p.62
Chapter 4.1.2 --- Functions of AtRab7 proteins in Arabidopsis cells --- p.63
Chapter 4.1.3 --- The Rab conversion maturation model --- p.63
Chapter 4.2 --- Future perspectives --- p.64
References --- p.73
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Uniacke, James. "Novel chloroplast compartments are sites of photosystem II biogenesis and mRNA management during stress in the chloroplast of Chlamydomonas reinhardtii." Thesis, 2009. http://spectrum.library.concordia.ca/976657/1/NR63359.pdf.
Full textAbstract:
Eukaryotic cells are highly compartmentalized. Many processes and metabolic pathways occur within specific organelles such as the nucleus, endoplasmic reticulum, Golgi apparatus, mitochondria, and peroxisomes. These compartments themselves are highly compartmentalized. In plants and algae, chloroplasts carry out photosynthesis, the biosynthesis of lipids, pigments, cofactors, amino acids, and function in the assimilation of S, P, and N. However, chloroplast cell biology has lagged behind that of other organelles. Classic models for the spatial organization of these processes are contradictory and based on EM and subcellular fractionation with no use of modern fluorescence microscopy. Here, chloroplast processes are revealed as highly compartmentalized within the chloroplast of Chlamydomonas reinhardtii with the first extensive use of fluorescence in situ hybridization, immunofluorescence staining and confocal microscopy. In Chapter 2, I propose that the processes underlying the biogenesis of thylakoids are compartmentalized in the chloroplast of C. reinhardtii. Chapter 4 describes the discovery of chloroplast stress granules, a compartment that manages mRNAs during oxidative stress. Chapter 3 assigned known targeting mechanisms to specific chloroplast proteins while identifying new examples of localized translation. Because the pyrenoid, a largely unexplored chloroplast compartment in most algae, plays a central role in many of my findings, and little is known about this compartment, I isolated it and characterized its proteome by mass spectrometry. The pyrenoid proteome consisted of proteins with roles in starch metabolism, CO 2 assimilation and nitrite reduction. Taken together, these findings reveal that the Chlamydomonas chloroplast is more highly compartmentalized and complex than has been appreciated and that it can be used as a model system to study fundamental cell biological questions. This work has advanced our understanding of the cell biology of chloroplasts and provides a new conceptual framework for research into chloroplast biogenesis
Books on the topic "Biogenesis of replication compartments"
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Mast, Christof, Friederike Möller, Moritz Kreysing, Severin Schink, Benedikt Obermayer, Ulrich Gerland, and Dieter Braun. Toward living nanomachines. Oxford University Press, 2018. http://dx.doi.org/10.1093/oso/9780199674923.003.0039.
Full textAbstract:
How does inanimate matter become transformed into animate matter? Living systems evolve by replication and selection at the molecular level and this chapter considers how to establish a synthetic, minimal system that can support molecular evolution and thus life. Molecular evolution cannot be explained by starting with high concentrations of activated chemicals that react toward their chemical equilibrium; persistent non-equilibria are required to maintain continuous reactivity and we especially consider thermal gradients as an early driving force for Darwinian molecular evolution. The temperature difference across water-filled compartments implements a laminar fluid convection with periodic temperature oscillations that allow for the melting and replication of DNA. Simultaneously, dissolved molecules are moved along the thermal gradient by an effect called thermophoresis. The combined result is an efficient molecule trap that exponentially favors long over short DNA and thus maintains complexity. Future experiments will reveal how thermal gradients could actively drive the Darwinian process of replication and selection.
Book chapters on the topic "Biogenesis of replication compartments"
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Swanson, Michele S., and Michael A. Bachman. "The Legionella pneumophila Life Cycle: Connections between Growth Phase, Virulence Expression, and Replication Vacuole Biogenesis." In Legionella, 74–81. Washington, DC, USA: ASM Press, 2014. http://dx.doi.org/10.1128/9781555817985.ch15.
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M. Pike, Colleen, Rebecca R. Noll, and M. Ramona Neunuebel. "Exploitation of Phosphoinositides by the Intracellular Pathogen, Legionella pneumophila." In Pathogenic Bacteria. IntechOpen, 2020. http://dx.doi.org/10.5772/intechopen.89158.
Full textAbstract:
Manipulation of host phosphoinositide lipids has emerged as a key survival strategy utilized by pathogenic bacteria to establish and maintain a replication-permissive compartment within eukaryotic host cells. The human pathogen, Legionella pneumophila, infects and proliferates within the lung’s innate immune cells causing severe pneumonia termed Legionnaires’ disease. This pathogen has evolved strategies to manipulate specific host components to construct its intracellular niche termed the Legionella-containing vacuole (LCV). Paramount to LCV biogenesis and maintenance is the spatiotemporal regulation of phosphoinositides, important eukaryotic lipids involved in cell signaling and membrane trafficking. Through a specialized secretion system, L. pneumophila translocates multiple proteins that target phosphoinositides in order to escape endolysosomal degradation. By specifically binding phosphoinositides, these proteins can anchor to the cytosolic surface of the LCV or onto specific host membrane compartments, to ultimately stimulate or inhibit encounters with host organelles. Here, we describe the bacterial proteins involved in binding and/or altering host phosphoinositide dynamics to support intracellular survival of L. pneumophila.
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Arakawa, Masashi, and Eiji Morita. "Zika virus infection and replication organelle biogenesis." In Zika Virus Impact, Diagnosis, Control, and Models, 49–57. Elsevier, 2021. http://dx.doi.org/10.1016/b978-0-12-820267-8.00005-4.
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Lill, Roland, Christoph Hergersberg, Helmut Schneider, Thomas Söllner, Rosemary Stuart, and Walter Neupert. "Chapter 21 General and exceptional pathways of protein import into sub-mitochondrial compartments." In Membrane Biogenesis and Protein Targeting, 265–76. Elsevier, 1992. http://dx.doi.org/10.1016/s0167-7306(08)60098-8.
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ANDREWS, DAVID W., and RICHARD A. RACHUBINSKI. "Secretion and Organelle Biogenesis: Problems in Targeting Proteins to Specific Subcellular Compartments." In Tip Growth In Plant and Fungal Cells, 317–43. Elsevier, 1990. http://dx.doi.org/10.1016/b978-0-12-335845-5.50015-x.
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Maynard Smith, John, and Eors Szathmary. "The evolution of templates." In The Major Transitions in Evolution. Oxford University Press, 1997. http://dx.doi.org/10.1093/oso/9780198502944.003.0008.
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In this chapter, we discuss the origin and early evolution of genetic replication. The argument is complex, so we start with a brief outline. Section 4.2 discusses the nature of replication. We draw a distinction between simple replicators, limited hereditary replicators and indefinite hereditary replicators. Continued evolution requires indefinite hereditary replicators: it seems that such replicators depend on some form of template reproduction. In section 4.3, we point out that there is an error threshold for the accuracy of replication: for a given total quantity of genetic information—for example, for a fixed number of bases—there is an upper limit on the error rate of replication. If the error rate rises above this limit, natural selection cannot maintain the information. This leads to what we have called Eigen's paradox. In the absence of specific enzymes, replication accuracy is low. Hence the total genome size must be small—almost certainly, less than 100 nucleotides. The genome is therefore too small to code for accurate replication machinery. There is a catch-22 situation: no enzymes without a large genome, and no large genome without enzymes. The next three sections discuss possible solutions to the paradox. Section 4.4 considers populations of replicating RNA molecules. We point out that the dynamics of replication are such as to lead to the stable coexistence of a diverse population, but we do not think that this constitutes a solution to the paradox. Section 4.5 discusses the hypercycle, a particular relationship between replicators that makes it possible for a greater total quantity of information to be maintained with a given accuracy of replication. We argue that the further evolution of hypercycles requires that they be enclosed within compartments, because otherwise they are sensitive to parasitic replicators. We also discuss, rather inconclusively, the possibility that, even in the absence of compartments, cooperation might evolve, by a processes analogous to kin selection, if the components of the hypercycle were confined to a surface. Finally, we discuss an alternative model, the stochastic corrector model. This also depends on the existence of compartments, but emphasizes the importance of stochastic effects arising if there are small numbers of each kind of molecule in a compartment. Essentially, small numbers serve to generate variation upon which selection can act.
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Lucchesi, John C. "Nuclear bodies." In Epigenetics, Nuclear Organization & Gene Function, 153–62. Oxford University Press, 2019. http://dx.doi.org/10.1093/oso/9780198831204.003.0013.
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The nucleus is subdivided into a number of compartments that are not enclosed by membranes and whose main functions are transcriptional regulation and RNA processing. Many of the same proteins are found in different compartments, highlighting the dynamic exchange of components. The perinuclear compartment (PNC) is a hallmark of a number of different cancers. Cajal bodies (CBs) are sites of assembly of small nuclear ribonucleic particles (snRNPs) that function in messenger RNA (mRNA) or ribosomal RNA (rRNA) processing and in the biogenesis of telomerase. Nuclear speckles contain pre-mRNA splicing components and proteins involved in every aspect of gene regulation. Paraspeckles are involved in the processing and maturation of micro RNAs (miRNAs). Promyelocytic leukemia (PML) nuclear bodies contain the PML protein that has tumor suppressor activity by preventing the inactivation of p53. Under conditions of stress, the number and size of PML nuclear bodies increases. Transcription factories are nuclear regions where several RNA polymerase II (RNAPII) complexes are transcribing several genes. The co-localization of genes in transcription factories may lead to their co-regulation.
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Thai, Khac-Minh, Quoc-Hiep Dong, Thi-Thanh-Lan Nguyen, Duy-Phong Le, Minh-Tri Le, and Thanh-Dao Tran. "Computational Approaches for the Discovery of Novel Hepatitis C Virus NS3/4A and NS5B Inhibitors." In Oncology, 482–518. IGI Global, 2017. http://dx.doi.org/10.4018/978-1-5225-0549-5.ch017.
Full textAbstract:
Nonstructural 5B (NS5B) polymerase and Nonstructural 3/4A (NS3/4A) protease have proven to be promising targets for the development of anti-HCV (Hepatitis C Virus) agents. The NS5B polymerase is of paramount importance in HCV viral replication; therefore, employing NS5B inhibitors was considered an effective way for the treatment of HCV. Identifying inhibitors against NS3/4A serine protease represents another attractive approach applied in anti-HCV drug discovery, which is evidenced by its crucial role of in the biogenesis of the viral replication activity. In this chapter, many different computational approaches including Quantitative Structure-Activity Relationship (QSAR) and virtual screening in anti-HCV drug discovery were considered and discussed in detail. Virtual Screening (VS) techniques, including ligand-based and structure-based, and QSAR have been utilized for the discovery of NS5B inhibitors. Moreover, using various in silico protocols and workflows, a number of studies have been conducted with an aim of identifying potential NS3/4A blockage agents.
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Thai, Khac-Minh, Quoc-Hiep Dong, Thi-Thanh-Lan Nguyen, Duy-Phong Le, Minh-Tri Le, and Thanh-Dao Tran. "Computational Approaches for the Discovery of Novel Hepatitis C Virus NS3/4A and NS5B Inhibitors." In Quantitative Structure-Activity Relationships in Drug Design, Predictive Toxicology, and Risk Assessment, 318–53. IGI Global, 2015. http://dx.doi.org/10.4018/978-1-4666-8136-1.ch009.
Full textAbstract:
Nonstructural 5B (NS5B) polymerase and Nonstructural 3/4A (NS3/4A) protease have proven to be promising targets for the development of anti-HCV (Hepatitis C Virus) agents. The NS5B polymerase is of paramount importance in HCV viral replication; therefore, employing NS5B inhibitors was considered an effective way for the treatment of HCV. Identifying inhibitors against NS3/4A serine protease represents another attractive approach applied in anti-HCV drug discovery, which is evidenced by its crucial role of in the biogenesis of the viral replication activity. In this chapter, many different computational approaches including Quantitative Structure-Activity Relationship (QSAR) and virtual screening in anti-HCV drug discovery were considered and discussed in detail. Virtual Screening (VS) techniques, including ligand-based and structure-based, and QSAR have been utilized for the discovery of NS5B inhibitors. Moreover, using various in silico protocols and workflows, a number of studies have been conducted with an aim of identifying potential NS3/4A blockage agents.
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Ross, David. "Condensation Reactions Synthesize Random Polymers." In Assembling Life. Oxford University Press, 2019. http://dx.doi.org/10.1093/oso/9780190646387.003.0011.
Full textAbstract:
Over the past half century of serious research on the origin of life, several schools of thought have emerged that focus on “worlds” and what came first in the pathway to the origin of life. One example is the RNA World, a term coined by Walter Gilbert after the discovery of ribozymes. Other examples include the Iron-Sulfur World of Günther Wächtershäuser and the Lipid World proposed by Doron Lancet and coworkers. Then we have a competition between “metabolism first” and “replication first” schools. The worlds and schools have the positive effect of sharpening arguments and forcing us to think carefully, but they also can lock researchers into defending their individual approaches rather than looking for patterns in a larger perspective. One of the main themes of this book is the notion that the first living cells were systems of functional polymers working together within membranous compartments. Therefore, it is best not to think of “worlds” and “firsts” as fundamentals but instead as components evolving together toward the assembly of an encapsulated system of functional polymers. At first the polymers will be composed of random sequences of their monomers, and the compartments will contain random assortments of polymers. Here, we refer to these structures as protocells which are being produced in vast numbers as they form and decompose in continuous cycles driven by a variety of impinging, free-energy sources. This chapter describes how thermodynamic principles can be used to test the feasibility of a proposed mechanism by which random polymers can be synthesized. There is a current consensus that early life may have passed through a phase in which RNA served as a ribozyme catalyst, as a replicating system, and as a means for storing and expressing genetic information. For this reason, we will use RNA as a model polymer, but condensation reactions also produce peptide bonds and oligopeptides. At some point in the evolutionary steps leading to life, peptides and RNA formed complexes with novel functional properties beyond those of the individual molecular species.