Literatura científica selecionada sobre o tema "Genomic vulnerability"
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Artigos de revistas sobre o assunto "Genomic vulnerability"
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Jacobs, Bette, Jason Roffenbender, Jeff Collmann, Kate Cherry, LeManuel Lee Bitsói, Kim Bassett e Charles H. Evans. "Bridging the Divide between Genomic Science and Indigenous Peoples". Journal of Law, Medicine & Ethics 38, n.º 3 (setembro de 2010): 684–96. http://dx.doi.org/10.1111/j.1748-720x.2010.00521.x.
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The new science of genomics endeavors to chart the genomes of individuals around the world, with the dual goals of understanding the role genetic factors play in human health and solving problems of disease and disability. From the perspective of indigenous peoples and developing countries, the promises and perils of genomic science appear against a backdrop of global health disparity and political vulnerability. These conditions pose a dilemma for many communities when attempting to decide about participating in genomic research or any other biomedical research. Genomic research offers the possibility of improved technologies for managing the acute and chronic diseases that plague their members. Yet, the history of biomedical research among people in indigenous and developing nations offers salient examples of unethical practice, misuse of data and failed promises. This dilemma creates risks for communities who decide either to participate or not to participate in genomic science research.
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Feulner, Philine G. D., e Ole Seehausen. "Genomic insights into the vulnerability of sympatric whitefish species flocks". Molecular Ecology 28, n.º 3 (29 de janeiro de 2019): 615–29. http://dx.doi.org/10.1111/mec.14977.
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Grauke, L. J., Bruce W. Wood e Marvin K. Harris. "Crop Vulnerability: Carya". HortScience 51, n.º 6 (junho de 2016): 653–63. http://dx.doi.org/10.21273/hortsci.51.6.653.
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Long-established native tree populations reflect local adaptations. Representation of diverse populations in accessible ex situ collections that link information on phenotypic expression to information on spatial and temporal origination is the most efficient means of preserving and exploring genetic diversity, which is the foundation of breeding and crop improvement. Throughout North America, sympatric Carya species sharing the same ploidy level tend to hybridize, permitting gene flow that contributes to regional diversity and adaptation. The topographic isolation of many fragmented populations, some of which are small, places native Carya populations of United States, Mexico, and Asia in a vulnerable position and justifies systematic collection and characterization. The characterization of indigenous Mexican pecan and other Carya populations will facilitate use for rootstocks and scion breeding and will contribute to pecan culture. The Asian species, as a group, are not only geographically isolated from North American species, but also occur in disjunct, fragmented populations isolated from other Asian species. Section Sinocarya includes the members of the genus most vulnerable to genetic loss. With all species, recognition of utility based on characterization of ex situ collections may contribute to the establishment of in situ reserves. Global Carya genetic resources should be cooperatively collected, maintained, characterized, and developed. The integration of crop wild relatives into characterization and breeding efforts represents a challenging opportunity for both domestic and international cooperation. Genomic tools used on the accessible collections of the National Collection of Genetic Resources for Pecans and Hickories (NCGR-Carya) offer great potential to elucidate genetic adaptation in relation to geographic distribution. The greatest progress will be made by integrating the disciplines of genetics, botany, pathology, entomology, ecology, and horticulture into internationally cooperative efforts. International germplasm exchange is becoming increasingly complicated by a combination of protectionist policies and legitimate phytosanitary concerns. Cooperative international evaluation of in situ autochthonous germplasm provides a valuable safeguard to unintended pathogen exchange associated with certain forms of germplasm distribution, while enabling beneficial communal exploration and directed exchange. This is threatened by the “proprietary” focus on intellectual property. The greatest risk to the productive development of the pecan industry might well be a myopic focus on pecan production through the lens of past practice. The greatest limitation to pecan culture in the western United States is reduced water quantity and quality; in the eastern United States the challenge is disease susceptibility; and insufficient cold hardiness in the northern United States. The greatest benefit for the entire industry might be achieved by tree size reduction through both improved rootstocks and scions, which will improve both nut production and tree management, impacting all areas of culture. This achievement will likely necessitate incorporation of crop wild relatives in breeding, broad cooperation in the testing leading to selection, and development of improved methods linking phenotypic expression to genomic characterization. The development of a database to appropriately house information available to a diverse research community will facilitate cooperative research. The acquisition of funds to pursue development of those tools will require the support of the pecan industry, which in the United States, is regionally fragmented and focused on marketing rather than crop development.
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Hettmer, Simone, Anna C. Schinzel, Daria Tchessalova, Nigel Richards, William C. Hahn e Amy J. Wagers. "Functional genomic screening reveals asparagine dependence as a metabolic vulnerability in sarcoma". Molecular and Cellular Pediatrics 2, Suppl 1 (2015): A3. http://dx.doi.org/10.1186/2194-7791-2-s1-a3.
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Schmidt-Kastner, Rainald. "Genomic approach to selective vulnerability of the hippocampus in brain ischemia–hypoxia". Neuroscience 309 (novembro de 2015): 259–79. http://dx.doi.org/10.1016/j.neuroscience.2015.08.034.
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Chan, Sock Hoai, e Joanne Ngeow. "Germline mutation contribution to chromosomal instability". Endocrine-Related Cancer 24, n.º 9 (setembro de 2017): T33—T46. http://dx.doi.org/10.1530/erc-17-0062.
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Genomic instability is a feature of cancer that fuels oncogenesis through increased frequency of genetic disruption, leading to loss of genomic integrity and promoting clonal evolution as well as tumor transformation. A form of genomic instability prevalent across cancer types is chromosomal instability, which involves karyotypic changes including chromosome copy number alterations as well as gross structural abnormalities such as transversions and translocations. Defects in cellular mechanisms that are in place to govern fidelity of chromosomal segregation, DNA repair and ultimately genomic integrity are known to contribute to chromosomal instability. In this review, we discuss the association of germline mutations in these pathways with chromosomal instability in the background of related cancer predisposition syndromes. We will also reflect on the impact of genetic predisposition to clinical management of patients and how we can exploit this vulnerability to promote catastrophic genomic instability as a therapeutic strategy.
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Dwyer, Donard S. "Genomic Chaos Begets Psychiatric Disorder". Complex Psychiatry 6, n.º 1-2 (2020): 20–29. http://dx.doi.org/10.1159/000507988.
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The processes that created the primordial genome are inextricably linked to current day vulnerability to developing a psychiatric disorder as summarized in this review article. Chaos and dynamic forces including duplication, transposition, and recombination generated the protogenome. To survive early stages of genome evolution, self-organization emerged to curb chaos. Eventually, the human genome evolved through a delicate balance of chaos/instability and organization/stability. However, recombination coldspots, silencing of transposable elements, and other measures to limit chaos also led to retention of variants that increase risk for disease. Moreover, ongoing dynamics in the genome creates various new mutations that determine liability for psychiatric disorders. Homologous recombination, long-range gene regulation, and gene interactions were all guided by spooky action-at-a-distance, which increased variability in the system. A probabilistic system of life was required to deal with a changing environment. This ensured the generation of outliers in the population, which enhanced the probability that some members would survive unfavorable environmental impacts. Some of the outliers produced through this process in man are ill suited to cope with the complex demands of modern life. Genomic chaos and mental distress from the psychological challenges of modern living will inevitably converge to produce psychiatric disorders in man.
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Razgour, Orly, Brenna Forester, John B. Taggart, Michaël Bekaert, Javier Juste, Carlos Ibáñez, Sébastien J. Puechmaille, Roberto Novella-Fernandez, Antton Alberdi e Stéphanie Manel. "Considering adaptive genetic variation in climate change vulnerability assessment reduces species range loss projections". Proceedings of the National Academy of Sciences 116, n.º 21 (6 de maio de 2019): 10418–23. http://dx.doi.org/10.1073/pnas.1820663116.
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Local adaptations can determine the potential of populations to respond to environmental changes, yet adaptive genetic variation is commonly ignored in models forecasting species vulnerability and biogeographical shifts under future climate change. Here we integrate genomic and ecological modeling approaches to identify genetic adaptations associated with climate in two cryptic forest bats. We then incorporate this information directly into forecasts of range changes under future climate change and assessment of population persistence through the spread of climate-adaptive genetic variation (evolutionary rescue potential). Considering climate-adaptive potential reduced range loss projections, suggesting that failure to account for intraspecific variability can result in overestimation of future losses. On the other hand, range overlap between species was projected to increase, indicating that interspecific competition is likely to play an important role in limiting species’ future ranges. We show that although evolutionary rescue is possible, it depends on a population’s adaptive capacity and connectivity. Hence, we stress the importance of incorporating genomic data and landscape connectivity in climate change vulnerability assessments and conservation management.
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Lee, Tae-Hee, Xuan C. Qiao, Tongyu Wu, Vladislav Kuzin, Xianzhen Zhou, Vijayalalitha Ramanarayanan, Laura Baranello e Philipp Oberdoerffer. "Abstract A024: Epigenetic control of topoisomerase 1 activity presents a cancer vulnerability". Cancer Research 84, n.º 1_Supplement (9 de janeiro de 2024): A024. http://dx.doi.org/10.1158/1538-7445.dnarepair24-a024.
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Abstract Genome integrity is inherently at risk due to the torsional constraints imposed by DNA transactions. Topoisomerase 1 (TOP1) is essential for genomic stability by removing DNA supercoils generated during replication and transcription. Aberrant stabilization of TOP1:DNA cleavage complexes (TOP1ccs), however, result in DNA lesions that drive transcription-associated mutation burden and are a cytotoxic consequence of many clinically used chemotherapeutic agents. What protects genomic regions prone to elevated torsional stress from the cytotoxic potential of TOP1 enzymes remains unknown. Here, we identify macroH2A1.1, the only nucleosome component with an inherent ability to bind the TOP1cc repair-essential poly(ADP-ribose) (PAR) protein modification, as an essential means to establish a TOP1-permissive chromatin environment. MacroH2A1.1 is one of two alternatively spliced isoforms of the macro-histone variant macroH2A1, and comparative proteomics between the two isoforms uncovered a macroH2A1.1-specific and PARP activity-dependent interaction with the TOP1cc repair effector TDP1 as well as downstream base excision repair (BER) factors XRCC1 and LIG3. Consequently, macroH2A1.1 loss or inactivation of its PAR-binding domain resulted in impaired XRCC1 recruitment to damaged DNA and defective TOP1cc turnover, while the macroH2A1.2 splice isoform is unable to bind PAR or protect from TOP1ccs. Genome-wide mapping of macroH2A1.1, TOP1 and TOP1-DNA adducts identified macroH2A1.1 as a regulatory hub for TOP1 activity that ensures transcriptional integrity by preventing excessive TOP1cc accumulation at transcription start sites. Impaired macroH2A1.1 splicing, a frequent cancer feature, correlated with sensitivity to TOP1 poisons in a pharmaco-genomic screen in breast cancer cells, and macroH2A1.1 inactivation mirrored this effect. Finally, we find that aberrant macroH2A1 alternative splicing in cancer correlates with BER-related mutation signatures. We propose that macroH2A1 alternative splicing serves as an epigenetic modulator of TOP1-associated genome maintenance and a potential cancer vulnerability. Citation Format: Tae-Hee Lee, Xuan C. Qiao, Tongyu Wu, Vladislav Kuzin, Xianzhen Zhou, Vijayalalitha Ramanarayanan, Laura Baranello, Philipp Oberdoerffer. Epigenetic control of topoisomerase 1 activity presents a cancer vulnerability [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr A024.
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Akimkin, V. G., T. A. Semenenko, K. F. Khafizov, S. V. Ugleva, D. V. Dubodelov, E. D. Sverdlov, A. S. Cherkashina et al. "Biosafety and Genomic Epidemiological Surveillance". Epidemiology and Vaccinal Prevention 23, n.º 5 (6 de novembro de 2024): 4–12. http://dx.doi.org/10.31631/2073-3046-2024-23-5-4-12.
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The problem of biological safety is extremely relevant today for all countries of the world because of the real and potential threats caused by biological agents that are dangerous to public health and the environment. Modern microorganisms are becoming increasingly aggressive towards humans, as clearly demonstrated by the COVID-19 pandemic, which has affected all aspects of people's lives and exposed the vulnerability of the healthcare system. According to the Decree of the President of the Russian Federation «On the Fundamentals of the State policy of the Russian Federation in the field of chemical and biological safety for the period up to 2025 and beyond» and the Federal Law «On Biological Safety in the Russian Federation», the main objectives of state policy are to reduce the risks of negative effects of biological factors on the population and the environment. Antimicrobial resistance, the emergence of new infections and the overcoming of interspecific barriers by microorganisms are of particular concern. Infectious disease agents with epidemic potential, such as Ebola, Zika, Marburg, Lassa, MERS-CoV and SARS-CoV viruses, continue to pose a high threat. To counteract new biological threats, Russia has created a scientific concept of future biosafety, focusing on the development of genomic epidemiological surveillance, digital transformation and mobile technologies. Effective management of epidemic processes requires constant monitoring of genetic changes in infectious agents and prompt response to new threats, which allows the VGARus platform created in Russia to monitor virus mutations. Thus, genomic epidemiological surveillance is becoming a key element of ensuring biological safety and scientific and technological development in Russia.
Teses / dissertações sobre o assunto "Genomic vulnerability"
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Lee, Kelvin Sze Yen. "A genomic approach to atherosclerotic plaque vulnerability". Thesis, University of Newcastle Upon Tyne, 2012. http://hdl.handle.net/10443/1678.
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BACKGROUND: Macrophages in atherosclerotic plaques are believed to play a central role in plaque instability. However, the cell-specific molecular mechanisms involved are incompletely characterized. To address this, we performed genome-wide gene expression analyses using microarrays on RNA extracted from macrophage-rich regions of stable and unstable human atheromatous plaques. METHODS AND RESULTS: Plaques derived from carotid endarterectomy specimens (n=118) were designated as stable or unstable according to clinical, radiological and histopathological criteria. Macrophage-rich regions were excised from unstable and stable plaques by laser microdissection. Transcriptional profiling of extracted RNA was carried out using Affymetrix U133plus2 microarrays. The expression profiles were characteristic of activated macrophages. Expression profiles from stable and unstable samples clustered into distinct groups. Nine hundred and fourteen genes differentially expressed between stable and unstable sample groups were identified at a false discovery rate of 10%. The findings were confirmed by real-time PCR for eleven of the twelve genes with the highest fold expression difference (p<0.05). The analysis of the gene expression of the twelve highest fold expression genes by their principal components demonstrated a distribution of the samples along an axis of stability-instability in gene expression space. More specifically, components of the PPAR/Adipocytokine signalling pathway were significantly differentially expressed (p=5.4x10-7) between stable and unstable plaques with greater expression in unstable plaques. Key components of the pathway, fatty acid binding protein 4 (FABP4) and leptin, showed nine-fold (p=0.0086) and five-fold (p=0.0012) greater expression in unstable plaques respectively. The immunohistochemistry of the protein products for FABP4 and Leptin confirmed their co-localisation with the macrophages in the plaque. CONCLUSION: Differences in gene expression signatures are present between macrophages isolated from stable and unstable human atheromatous plaques. Components of the PPAR/adipocytokine signalling pathway, specifically FABP4 and Leptin, are expressed at higher levels in macrophages from unstable plaques. These findings suggest that down-regulation of PPAR/adipocytokine signalling within plaques may have therapeutic potential.
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Kaczmarek, Thomas. "Reconstruire et prédire les dynamiques évolutives du fonio (Digitaria exilis, Digitaria iburua) : domestication, diversité cultivée et potentiel adaptatif". Electronic Thesis or Diss., Université de Montpellier (2022-....), 2024. http://www.theses.fr/2024UMONG025.
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La diversité des plantes cultivées et des savoirs associés représente une solution précieuse pour le développement de systèmes robustes et résilients face à l’accélération des crises socio-écologiques. En Afrique de l’Ouest, les paysans et paysannes cultivent de nombreuses variétés et espèces traditionnelles, dont deux espèces communément appelées fonio (Digitaria exilis, Digitaria iburua). Malgré l’importance reconnue aux fonios pour leurs propriétés agronomiques et nutritionnelles, ces céréales n’ont reçu qu’une attention limitée de la part de la recherche mondiale. Dans cette thèse, ces deux cultures sont considérées d’un point de vue évolutif, de la reconstruction des dynamiques liées à leur domestication, à la prédiction de l’évolution temporelle et spatiale de leur diversité nécessaire à leur adaptation future au changement climatique. Dans le chapitre 1, nous étudions les relations génétiques et évolutives entre les espèces cultivées et leurs apparentés sauvages avec le reséquençage de génomes complets. La combinaison d’approches génomiques permet d’affirmer l’indépendance des domestications de chacune des espèces. Dans le chapitre 2, l’analyse de 1539 accessions de D. exilis génotypées avec des marqueurs microsatellites nous permet de produire pour la première fois une image complète de la structure génétique du fonio sur l’ensemble de son aire de répartition. Les données passeport ont été rassemblées pour constituer la plus grande collection internationale de ressources génétiques du fonio. Celle-ci est dorénavant accessible via une application Shiny qui permet d’explorer le profil génétique des populations de fonio en lien avec la géographie. Ce travail est le socle sur lequel l’échantillonnage du dernier chapitre repose pour étudier la vulnérabilité des ressources génétiques du fonio aux évolutions climatiques. A l’aide de modélisations prospectives de la diversité génomique et des données issues d’un essai expérimental, nous avons identifié les zones et populations les plus vulnérables, puis proposé des stratégies de migrations assistées pouvant atténuer les impacts négatifs du changement climatique. Enfin, en plus de l’acquisition de connaissances fondamentales, cette thèse souligne l’importance et la nécessité de développer des collaborations multi-spatiales et multi-échelles, dans un cadre pluridisciplinaire, dans le but de conserver et de valoriser la diversité des espèces traditionnellesCrop diversity and associated knowledge represent a valuable solution for developing robust and resilient systems in the face of accelerating socio-ecological crises. In West Africa, farmers grow many traditional varieties and species, including two species commonly known as fonio (Digitaria exilis, Digitaria iburua). Despite the recognised importance of fonio species for their agronomic and nutritional properties, these cereals have received little attention from mainstream research. This thesis examines these two crops from an evolutionary point of view, from reconstructing the dynamics associated with their domestication, to predicting the temporal and spatial evolution of the diversity necessary for adaptation to climate change. In Chapter 1, we investigate the genetic and evolutionary relationships between cultivated species and their wild relatives with whole genome resequencing of individuals. The combination of genomic approaches has enabled us to establish the independence of the domestication of each species. In Chapter 2, the analysis of 1539 D. exilis accessions genotyped with microsatellite markers allows us, for the first time, to obtain a complete picture of the fonio genetic structure across its cultivation area. The passport data have been compiled to create the largest international collection of fonio genetic resources. It can now be accessed via a Shiny application that allows users to explore the genetic profile of fonio populations in relation to geography. This work allowed us to design an appropriate sampling strategy for the final chapter which focus on the vulnerability of fonio genetic resources to climate change. By modelling future genomic diversity and conducting an experimental trial, we have identified the most vulnerable areas and populations, and then proposed assisted migration strategies to mitigate the negative impacts of climate change. Finally, in addition to the acquisition of essential knowledge, this thesis highlights the importance and necessity of developing multi-spatial and multi-scale collaborations within a multi disciplinary framework, in order to conserve and make an effective use of the diversity of traditional species
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Zimmermann, Petra, Tanja Brückl, Roselind Lieb, Agnes Nocon, Marcus Ising, Katja Beesdo e Hans-Ulrich Wittchen. "The Interplay of Familial Depression Liability and Adverse Events in Predicting the First Onset of Depression During a 10-Year Follow-up". Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2013. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-111276.
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Background: The aim of the present article is to explore interaction and correlation effects between familial depression liability and selected adverse (separation and traumatic) events in predicting the first onset of a major depressive episode (MDE) in a 10-year prospective longitudinal community survey.
Methods: Analyses are based on 1982 subjects (14 to 24 years at baseline) without baseline MDE who participated during the whole study period and for whom diagnostic information about psychopathology in both parents was available. The offspring’s familial depression liability was determined by aggregating information on parental depressive symptoms obtained from family history data and direct interviews with parents. Data were assessed with the Munich-Composite International Diagnostic Interview according to its DSM-IV algorithms.
Results: Adverse events predicted a substantially increased incidence of MDE among respondents with familial liability but not in those without familial liability. There was a significant interaction between familial liability and traumatic events with the strongest effect for the number of severe traumatic events (risk difference = 11.3%; 95% confidence interval = 3.55–19.15). Associations with familial liability were most pronounced for separation events.
Conclusions: Adverse events are particularly pathogenic in individuals with familial liability. The involvement of interactions and correlations between familial liability and adversity might depend on type, severity, and number of events. Both processes are suggested to be concomitant rather than exclusive.
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Zimmermann, Petra, Tanja Brückl, Roselind Lieb, Agnes Nocon, Marcus Ising, Katja Beesdo e Hans-Ulrich Wittchen. "The Interplay of Familial Depression Liability and Adverse Events in Predicting the First Onset of Depression During a 10-Year Follow-up". Technische Universität Dresden, 2008. https://tud.qucosa.de/id/qucosa%3A26838.
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Background: The aim of the present article is to explore interaction and correlation effects between familial depression liability and selected adverse (separation and traumatic) events in predicting the first onset of a major depressive episode (MDE) in a 10-year prospective longitudinal community survey.
Methods: Analyses are based on 1982 subjects (14 to 24 years at baseline) without baseline MDE who participated during the whole study period and for whom diagnostic information about psychopathology in both parents was available. The offspring’s familial depression liability was determined by aggregating information on parental depressive symptoms obtained from family history data and direct interviews with parents. Data were assessed with the Munich-Composite International Diagnostic Interview according to its DSM-IV algorithms.
Results: Adverse events predicted a substantially increased incidence of MDE among respondents with familial liability but not in those without familial liability. There was a significant interaction between familial liability and traumatic events with the strongest effect for the number of severe traumatic events (risk difference = 11.3%; 95% confidence interval = 3.55–19.15). Associations with familial liability were most pronounced for separation events.
Conclusions: Adverse events are particularly pathogenic in individuals with familial liability. The involvement of interactions and correlations between familial liability and adversity might depend on type, severity, and number of events. Both processes are suggested to be concomitant rather than exclusive.
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Gaudeau, Albane. "Conversion du cancer du sein triple-négatif par la modulation épigénétique Cell-Based siRNA Screens Highlight Triple-Negative Breast Cancer Cell Epigenetic Vulnerability True Value of RNAi Screens Beyond On-Target Effects Du criblage à haut contenu à la déconvolution de cibles : nouvelle donne pour les approches phénotypiques". Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASL048.
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Les travaux de recherche que présente cette thèse sont le fruit de collaborations fructueuses entre mon entreprise d’accueil, l’Institut de Recherches SERVIER, mon laboratoire d’accueil, la plateforme BioPhenics de l’Institut Curie, et moi-même préparant mon doctorat à l’Ecole Doctorale CBMS de l’Université Paris-Saclay. Des partenariats internationaux ont également permis de générer et d’enrichir de multiples données dans un même but : identifier de nouvelles cibles thérapeutiques pour le traitement du cancer du sein triple-négatif (TNBC, Triple-negative breast cancer). Le cancer TNBC est une forme de cancer mammaire caractérisée par l’absence des récepteurs aux œstrogènes (ER, Estrogen Receptor), à la progestérone (PR, Progesterone receptor), et du récepteur de facteur de croissance épidermique humain 2 (HER2, Human epidermal growth factor receptor 2), touchant près de 20% des femmes diagnostiquées avec un cancer mammaire. Par l’absence de ces récepteurs, les patientes ne sont éligibles ni aux thérapies hormonales ni aux thérapies ciblées anti-HER2. Alors que le cancer TNBC est enrichi en cellule-souches cancéreuses (CSC) et que des dérégulations épigénétiques ont été identifiées dans les voies de signalisation des CSC des TNBC, nous avons émis l'hypothèse que les mécanismes épigénétiques pourraient être modulés et aboutir à deux phénotypes : un impact sur la viabilité des cellules d'une part, et un effet sur l'expression de HER2 de façon à sensibiliser les cellules aux thérapies anti-HER2 existantes d'autre part. Afin de vérifier ces hypothèses, nous avons réalisé des cribles de génomique fonctionnelle en siRNA ciblant 863 modulateurs épigénétiques par des approches à haut débit et haut contenu. Bien que l’utilisation de siRNA représente une approche puissante, le risque d’effets hors cible est important. Afin de renforcer la découverte de hits spécifiques et de limiter l’identification de hits non-spécifiques, différentes stratégies ont été mises en place pour les deux études. Alors que l’identification de gènes impliqués dans l’expression de HER2 est toujours à l’étude, nous avons identifié 3 gènes clés pour la viabilité des cellules TNBC, parmi lesquels CHAF1A, dont le rôle dans la viabilité des cellules TNBC est identifié pour la première fois. Aussi, suite à des analyses bioinformatiques réalisées à partir des résultats générés en viabilité, les effets non spécifiques à la cible initiale ont été considérés comme sources de hits potentiels, permettant d’envisager de nouvelles approches de génomique fonctionnelleResearch presented in this thesis manuscript is the result of a fruitful collaboration between my host company, Institut de Recherches SERVIER, my host laboratory, BioPhenics Laboratory at Institut Curie, and I, preparing my PhD at the doctoral school CBMS at Université Paris-Saclay. International partnerships also led to the generation of numerous data towards the same purpose: identifying novel therapeutic targets in triple-negative breast cancer (TNBC) treatment. TNBC is a breast cancer subtype characterized by its ER(Estrogen receptor)-, PR(Progesterone receptor)- and HER2(Human epidermal growth factor receptor 2)-negative phenotype, affecting almost 20% of breast cancer diagnosed women. In the absence of these receptors, patients cannot respond neither to hormone therapy nor anti-HER2 targeted therapies. While TNBC is enriched in cancer-stem cells (CSC) and epigenetic deregulations were identified in TNBC CSC signaling pathways, we supposed that epigenetic mechanisms could be modulated to result in two phenotypes : an impact on TNBC cell viability, and an impact on HER2 expression in order to sensitize cells to existing anti-HER2 therapies. To investigate these hypotheses, we performed siRNA functional genomics screening targeting 863 epigenetic modulators through high-throughput and high-content approaches. Although using siRNA represents a powerful approach, the risk of off-target effects is important. In order to reinforce on-target hits discovery and to prevent the identification of non-specific hits, various strategies were used for the two studies. While the identification of genes involved in HER2 expression is currently in progress, we identified 3 key genes for TNBC cell viability, including CHAF1A for which the role in TNBC cell viability was never revealed. Also, following bioinformatic analyses performed from viability data, off-target effects were considered as sources of potential hits, highlighting the potential of a new functional genomics screening approach
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Larsson, Andreas. "Fornlämningars risk och sårbarhet till följd av vintervägsaltning på det kommunala– och statliga vägnätet i ett förändrat klimat : Litteratur– och fältstudie om korrosion av artefakter, samt identifiering av riskområden genom en GIS–analys i Södermanland och Västmanland". Thesis, Umeå universitet, Institutionen för idé- och samhällsstudier, 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-175946.
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Archaeological artefacts excavated today are in a worse preserved state compare to those artefacts found before 1945. Previous research highlighted soil acidification as the main cause. However, not much research has been done to analyse other causalities, such as the spread of road salt during the wintertime and the potential deterioration that salt (sodium chloride) might cause on the physical cultural heritage. Nonetheless, it is proven that salt causes corrosion on infrastructure and on porous stone, masonry, and other composite materials in buildings. The aim of this work is to investigate how road salt move from the road surface (municipal– and state roads) and beyond, what factors might contribute to increased geographical spread and how we can limit the potential risk of damage associated with the spread of road salts to ancient historical sites. The research methods presented in this paper is a mix of field sampling study together with GIS– and literature analysis. The results show that the road salts spread according to an exponential decaying rate, where most of the road salts being spread 5–10 meters beyond the roadside. This means that cultural heritage sites within this buffer–area could be susceptible to salt induced damage to physical structures and deposited artefacts made from metals, rock, brick, and other material. Thereby it is pivotal to highlight the possible actions that can prevent the spread of road salts in a geographical landscape, and its effect on the physical cultural heritage.
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Fonseca, Casals Francina. "Pharmacogenomic study of oppioid addicts in methadone treatment / Francina Fonseca Casals". Doctoral thesis, Universitat Pompeu Fabra, 2010. http://hdl.handle.net/10803/7234.
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Although the well established efficacy of methadone maintenance treatment (MMT) in the opioid dependence disorder, there is a group of patients that are poor responders. The study of the influence of methadone pharmacodynamics and pharmacokinetics in dose requirements and program outcome remains still controversial. The aim of this dissertation is to study the pharmacodynamic and pharmacokinetic factors involved in the methadone maintenance treatment efficacy. The study recruited opioid dependence patients (DSM-IV criteria) from a MMT community program. Patients were clinically assessed and blood samples were obtained in order to evaluate methadone plasma concentrations of (R,S)-, (R) and (S)- methadone. Allelic variants of genes encoding the following proteins were assessed: BDNF, OPRM1, MYOCD, mGluR6, mGluR8, CRY1, NR4A2, 1q31.2 (rs965972), 2q21.2 (rs1867898), CYP3A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19 and P-glycoprotein. Responders and non-responders were defined by means of illicit opioid consumption detected in random urinalyses.
Differences in response status were found depending on different single nucleotide polymorphisms (SNPs of genes encoding for BDNF, MYOCD and GRM6. The CYP2D6 metabolizing phenotype was associated with response to MMT, and also with methadone dosage requirement and methadone plasma concentrations.
Els programes de manteniment amb metadona (PMM) han demostrat eficàcia en el tractament del trastorn per dependència d'opiacis malgrat la persistència de pacients amb mala resposta al tractament. L'estudi dels factors farmacodinàmics i farmacocinètics implicats en la resposta terapèutica ofereix resultats controvertits. L'objectiu de la tesi doctoral que es presenta és estudiar els factors farmacodinàmics i farmacocinètics de la metadona que poden estar implicats en l'eficàcia del tractament. S'han inclòs pacients ambulatoris diagnosticats de trastorn per dependència d'opiacis (segons criteris DSM-IV) en PMM. Els pacients s'han avaluat a nivell clínic i s'han obtingut mostres de sang per a l'estudi de les concentracions plasmàtiques de (R,S)-, (R) i (S)- metadona. S'han estudiat també les variants al·lèliques dels gens que codifiquen per: BDNF, OPRM1, MYOCD, mGluR6, mGluR8, CRY1, NR4A2, 1q31.2 (rs965972), 2q21.2 (rs1867898), CYP3A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19 i P-glicoproteïna. La mostra s'ha dividit en responedors i no responedors en funció del nombre de controls d'orina positius per a heroïna en analítiques realitzades de forma aleatòria.
Es van detectar diferències en resposta al tractament segons les variants dels gens codificants per a BDNF, MYOCD i GRM6. També es va detectar una associació entre el fenotip de CYP2D6, la resposta al tractament, la dosi requerida de metadona i les concentracions plasmàtiques.
Livros sobre o assunto "Genomic vulnerability"
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Rahimzadeh, Vasiliki, Karine Sénécal, Erika Kleiderman e Bartha M. Knoppers. Minors and incompetent adults: A tale of two populations. Oxford University Press, 2017. http://dx.doi.org/10.1093/oso/9780198786832.003.0019.
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The participation of vulnerable populations in biomedical research—such as minors and incompetent adults—has in the past, and will continue to be a central consideration in bioethics considering they warrant special protections against potential rights violations and exposure to undue risk. These populations, however, should not be excluded from the opportunity to benefit from scientific progress through their research participation. The promises of personalized medicine for improved diagnosis and treatment of pediatric diseases further underscores this pressing need for their inclusion. This chapter provides both a retrospective and prospective analysis of research participation, with a special focus on the involvement of minors and incompetent adults in the data-intensive research typical of personalized medicine and genomic translation. The authors propose reverse vulnerability as one conceptual lens through which to examine the ethical intersectionalities associated with data-intensive research participation within both populations. The chapter includes a discussion of how situational vulnerabilities unfold for minors and incompetent adults while participating in data-intensive research, as well as how these vulnerabilities are implicated in future ethics governance in the post genomic era.
Capítulos de livros sobre o assunto "Genomic vulnerability"
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Singh, Ashutosh, Rehan Fazal, Upasana Sahu, Manoj Kumar, Sandeep Bhatia, Aniket Sanyal e Naveen Kumar. "Zoonotic Origin, Genomic Organization, Transmission, and Mutation of SARS-CoV-2". In SARS-CoV-2 Variants and Global Population Vulnerability, 1–18. New York: Apple Academic Press, 2024. http://dx.doi.org/10.1201/9781003467939-1.
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Evanega, Sarah Davidson, Ravi P. Singh, Ronnie Coffman e Michael O. Pumphrey. "The Borlaug Global Rust Initiative: Reducing the Genetic Vulnerability of Wheat to Rust". In Genomics of Plant Genetic Resources, 317–31. Dordrecht: Springer Netherlands, 2013. http://dx.doi.org/10.1007/978-94-007-7575-6_13.
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Goldman, David. "The Genetic Basis of Addictive Disorders". In Neurobiology of Mental Illness, editado por Antonello Bonci e Nora D. Volkow, 696–705. Oxford University Press, 2013. http://dx.doi.org/10.1093/med/9780199934959.003.0052.
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The quantitative inheritance of addictions presaged identification of genes modulating risk. Vulnerability is mediated both by agent-specific and non-specific factors. Genomic views include Genome Wide Association which detected CHRNA5, a nicotinic receptor subunit that modulates vulnerability to smoking. Sequencing detected a population-specific stop codon in HTR2B, a serotonin receptor that modulates impulsivity and other addiction-related processes. The loci identified account for a small portion of inherited liability. In several instances larger effects have been observed on processes such as emotionality, impulsivity and metabolism that mediate vulnerability. Although we do not possess a set of genetic markers predictive of treatment response, several genes including OPRM1 which has been linked to response of alcoholic patients to naltrexone, have predictive value.
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Goldman, David, e Danielle Sambo. "Genetics of Substance Use Disorders". In Charney and Nestler's Neurobiology of Mental Illness, editado por Nora Volkow e Yavin Shaham, 621–34. 6a ed. Oxford University PressNew York, 2025. https://doi.org/10.1093/med/9780197640654.003.0045.
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Abstract Substance use disorders (SUDs) are influenced by genes, environment, and gene × environment interactions, leading to different levels and kinds of vulnerability. Some genes are substance specific, including genes that mediate drug metabolism or receptor binding. Others are nonspecific, including genes influencing reward, stress resiliency, or executive function, and are thus pleiotropic, leading to cross-transmission and comorbidity of SUDs and other disorders. Genome-wide association studies have revealed many SUD genes, including some in known pathways to addiction. Most functional loci are unknown, but polygenic scores are accounting for an increasing fraction of genetic liability. The identification of rare and uncommon variants with roles in SUDs is expanding, with some being “private” to certain populations, underscoring the need to increase diversity in SUD genetic studies. Together with multiomic data including transcriptome and epigenome, genomic studies are identifying new pathways to SUDs and generating novel targets for treatment and prevention.
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Gray, Joshua C., Sandra Sanchez-Roige, Abraham A. Palmer, Harriet de Wit e James MacKillop. "Genetics of decision-making". In Genes, brain, and emotions, 188–202. Oxford University Press, 2019. http://dx.doi.org/10.1093/oso/9780198793014.003.0013.
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Persistent maladaptive decision-making is central to several psychiatric conditions, particularly addiction. Decision-making measures may serve as promising intermediate phenotypes (i.e. intervening mechanisms that link genetic variation to clinical vulnerability) and thus elucidate biological mechanisms that increase risk for addiction and related psychiatric disorders. This chapter focuses on the heritability and specific genetic correlates of the three most widely studied experimental measures of decision-making: impulsivity, measured by delayed reward discounting; disadvantageous decision-making, measured by the Iowa Gambling Task; and risk sensitivity, measured by the Balloon Analogue Risk Task. Despite some evidence of heritability for all phenotypes, the candidate gene studies reveal inconsistent findings. The extant literature is limited by small sample sizes, and a focus on select candidate genes, primarily related to dopaminergic and serotonergic systems. To advance the science, research will need to aggregate studies, increase sample sizes, explore subpopulations, and utilize genome-wide association studies to expand the genomic scope.
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Smith, Moyra. "Impact Of The Environment On The Genome". In Translational Researchin Genetics and Genomics, 118–26. Oxford University PressNew York, NY, 2008. http://dx.doi.org/10.1093/oso/9780195313765.003.0008.
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Abstract Changes in DNA chemical composition, integrity, or structure may be induced through endogenous or exogenous factors, the latter of which may be chemical or physical factors. Genomic instability may occur as a direct or indirect result of environmental factors. The interactions between the environment and germinal tissues (ovary, eggs, testes, and sperm) and interaction between the environment and the developing organism during critical periods of vulnerability are of particular concern. Insight into agents that damage DNA and into mechanisms of DNA repair have been in part derived through studies on hereditary disorders characterized by a tendency to develop tumors.
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Civan, Peter, Renaud Rincent, Alice Danguy-Des-Deserts, Jean-Michel Elsen e Sophie Bouchet. "Population Genomics Along With Quantitative Genetics Provides a More Efficient Valorization of Crop Plant Genetic Diversity in Breeding and Pre-breeding Programs". In Population Genomics. Cham: Springer International Publishing, 2021. http://dx.doi.org/10.1007/13836_2021_97.
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AbstractThe breeding efforts of the twentieth century contributed to large increases in yield but selection may have increased vulnerability to environmental perturbations. In that context, there is a growing demand for methodology to re-introduce useful variation into cultivated germplasm. Such efforts can focus on the introduction of specific traits monitored through diagnostic molecular markers identified by QTL/association mapping or selection signature screening. A combined approach is to increase the global diversity of a crop without targeting any particular trait.A considerable portion of the genetic diversity is conserved in genebanks. However, benefits of genetic resources (GRs) in terms of favorable alleles have to be weighed against unfavorable traits being introduced along. In order to facilitate utilization of GR, core collections are being identified and progressively characterized at the phenotypic and genomic levels. High-throughput genotyping and sequencing technologies allow to build prediction models that can estimate the genetic value of an entire genotyped collection. In a pre-breeding program, predictions can accelerate recurrent selection using rapid cycles in greenhouses by skipping some phenotyping steps. In a breeding program, reduced phenotyping characterization allows to increase the number of tested parents and crosses (and global genetic variance) for a fixed budget. Finally, the whole cross design can be optimized using progeny variance predictions to maximize short-term genetic gain or long-term genetic gain by constraining a minimum level of diversity in the germplasm. There is also a potential to further increase the accuracy of genomic predictions by taking into account genotype by environment interactions, integrating additional layers of omics and environmental information.Here, we aim to review some relevant concepts in population genomics together with recent advances in quantitative genetics in order to discuss how the combination of both disciplines can facilitate the use of genetic diversity in plant (pre) breeding programs.
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Doshi, Tina, e Arissa Torrie. "Pain Genomics". In Pain Management in Vulnerable Populations, 36–58. Oxford University PressNew York, 2024. http://dx.doi.org/10.1093/med/9780197649176.003.0003.
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Abstract Due to a combination of both intrinsic (biological) and extrinsic (environmental) factors, pain vulnerability is highly variable across individuals. Intrinsic factors include genetics and genomics, which may be differentially influenced by extrinsic factors to create a unique biochemical profile that influences pain perception, processing, and treatment response. This chapter discusses hereditary pain conditions that inform understanding of pain vulnerability, as well as the genetic, epigenetic, proteomic, metabolomic, microbiome, and environmental factors (including pharmacotherapy) that can contribute to pain sensitivity, susceptibility, and response to analgesics. Consideration of these genetic and molecular factors can help identify patients vulnerable to pain and offer a precision medicine approach to pain treatment.
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"Vulnerability of the Science and Evidence Base of US Medicine". In Personal Genome Medicine, 202–98. Cambridge University Press, 2023. http://dx.doi.org/10.1017/9781009293341.006.
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Lynch, Michael R. "Origins of Organismal Complexity". In Evolutionary Cell Biology, 636–54. Oxford University PressOxford, 2024. http://dx.doi.org/10.1093/oso/9780192847287.003.0024.
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Abstract Rather than being an inexhaustible search for ways to construct more complex organisms, selection instead favours simplicity. Observations from the microbial world show that, despite their tendency not to gravitate to more complex forms, microbes are capable of doing so when the appropriate ecological opportunities are present. Although a substantial increase in genome size accompanied the emergence of eukaryotes from prokaryotes, most of it involves non-coding and non-functional DNA, particularly in multicellular lineages. This considerable bioenergetic and mutational burden was an inevitable outcome of the increased tendency of random genetic drift to overpower natural selection’s ability to oppose insertions of excess DNA. Further reorganization of the ancestral eukaryotic genome by gene-duplication events, followed by gene loss and subfunctionalization, led to new reproductively isolated lineages and encouraged transitions of homomeric molecular complexes to heteromeric forms. Ecological opportunity played a central role in the emergence of land plants and animals, but the evolution of complex multicellularity relied more on division of labor among cell types than on the emergence of new gene functions. Multicellular lineages experienced a further reduction in effective population sizes, imposing additional downstream costs including reduced growth-rate capacity, increased energetic cost and mutational vulnerability of genomes, gratuitous investment in overly complex cellular features, and the constant threat of mutant somatic cheater cells. The paths down which evolution proceeds are constrained by both the population-genetic environment and historical cellular contingencies, and this provides a mechanistic basis for understanding all aspects of biodiversity across the Tree of Life.
Trabalhos de conferências sobre o assunto "Genomic vulnerability"
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Gardner, Heather L., Karthigayini Sivaprakasam, Natalia Briones, William Hendricks e Cheryl A. London. "Abstract B026: The genomic landscape of canine osteosarcoma implicatesDMDas a therapeutic vulnerability". In Abstracts: AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; October 26-30, 2019; Boston, MA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1535-7163.targ-19-b026.
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Peeper, Daniel S., David Vredevoogd e Thomas Kuilman. "Abstract B033: T-cell-induced tumor vulnerability discovery in an IFNγ-independent genomic landscape". In Abstracts: Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; September 30 - October 3, 2018; New York, NY. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/2326-6074.cricimteatiaacr18-b033.
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Hettmer, Simone, Anna C. Schinzel, Daria Tchessalova, Nigel GJ Richards, William C. Hahn e Amy J. Wagers. "Abstract 1187: Functional genomic screening reveals asparagine dependence as a metabolic vulnerability in sarcoma". In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-1187.
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Kiezun, Adam, Jennifer Perry, Peter Tonzi, Eliezer Van Allen, Scott L. Carter, Sylvan Baca, Ami Bhatt et al. "Abstract A41: Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma". In Abstracts: AACR Special Conference: Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; November 3-6, 2013; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.pedcan-a41.
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Ni, Yingjia, Keon R. Schmidt, Barnes A. Werner, Jenna K. Koenig, Ian H. Guldner, Patricia M. Schnepp, Xuejuan Tan et al. "Abstract 4841: Functional genome-wide screening identifies triple-negative breast cancer cell cycle-dependent vulnerability driven by genomic gain of death effector domain-containing protein". In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-4841.
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Paolella, Brenton R., William J. Gibson, Laura M. Urbanski, John A. Alberta, Travis I. Zack, Pratiti Bandopadhayay, Caitlin A. Nichols et al. "Abstract 4369: Genome-wide copy number dependency analysis identifies partial copy loss of SF3B1 as a novel cancer vulnerability". In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-4369.
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Oliveira, Evelyn, Thaís Hudson Carneiro, Tiffany Marques dos Santos, Everaldo Soares Muniz e Claudia Cristina Soares Silva-Muniz. "Influence of cardiovascular risk factors for hereditary hypertension in the homeless population of São Paulo, Brazil". In III SEVEN INTERNATIONAL MULTIDISCIPLINARY CONGRESS. Seven Congress, 2023. http://dx.doi.org/10.56238/seveniiimulti2023-098.
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Introduction: Systemic arterial hypertension (SAH) is a public health problem, affecting about 30% of Brazilians. Due to the multifactorial condition, its development, in cases of genetic predisposition, results from the association of genes and environmental factors, such as: sedentary lifestyle, stress, diet, dyslipidemia, obesity, among others. The hypertensive risk factors (RF) in the homeless population (PSR) gain relevance, due to their situation of vulnerability. Objective: To highlight the impact of cardiovascular RF on the development of hereditary hypertension in the homeless. Methodology: Exploratory, cross-sectional and quantitative study. Conducted by pre-structured questionnaire, approved by the Institutional Ethics Committee, CAAE: 21519413.40000.5511, applied between November 2021 and July 2022, in the central region of São Paulo; evaluating the lifestyle and cardiovascular RF of 119 volunteers aged 18 to 60 years, chosen for convenience. Results and Discussion: It was identified that 51.26% reported a family history of SAH. Of these, the average blood pressure was 154x102 mmHg, reporting that 21% suffer from stress, 44% are sedentary and 43% consume high concentrations of sodium in food. Therefore, it is possible to show that the presence of RF determines the tendency to express a hypertensive gene. Such factors play a crucial role in the activation of the sympathetic nervous system and renin-angiotensin system; leading to chemical modifications in the genome, characterizing the onset of SAH in genetically predisposed individuals. Conclusion: We highlight behaviors in the RSP that contribute to the development of hereditary SAH. Consequently, a multidisciplinary approach becomes essential in an attempt to find effective ways to reintegrate this population, aiming to change lifestyle habits. Therefore, just as modifiable RFs influence the manifestation of the disease, environmental stimuli resulting from healthy habits will induce essential changes against the inheritance of the hypertensive trait. Thus, we envision new studies on this theme, strengthening existing public policies and implementing new ones, with the preventive purpose.