73 research outputs found
Use of nutrigenomics in understanding mechanisms underlying the vascular protective effects of dietary polyphenols
No full textPresenting author: Dragan Milenkovic The Second International Congress of Translational Research in Human Nutrition is organised by the Research Centre in Human Nutrition (CRNH) of Auvergne, of which INRA is a member, in collaboration with NuGO, European Association of universities and research institutes in the field of nutrigenomicsPresenting author: Dragan Milenkovic The Second International Congress of Translational Research in Human Nutrition is organised by the Research Centre in Human Nutrition (CRNH) of Auvergne, of which INRA is a member, in collaboration with NuGO, European Association of universities and research institutes in the field of nutrigenomicsEpidemiological, human and animal studies suggest a protective role of dietary polyphenols against cardiovascular diseases. Their capacity to modulate genes expression and signaling pathways may be involved in their cardiovascular protective effects but the mechanisms remain still unknown. The aim of our research is to investigate the cardiovascular protective property of polyphenols and decipher underlying molecular mechanisms using holistic nutrigenomics approach. In murin models of atherosclerosis, 16-week supplementation with nutritionally-relevant doses of polyphenols (catechin, bilberry anthocyanins, naringin or curcumin) decreased progression of atherosclerosis. Nutrigenomic studies of aorta indicated that polyphenols modified the expression of hundreds genes and functional analysis of these data identified a cluster of common pathways related to cell-cell adhesion, cell junctions, focal adhesion, and cell cytoskeleton. These processes regulate adhesion and transendothelial migration of monocytes into the intima of blood vessels, the initial step of atherosclerosis development. Immunofluorescence analysis of the aortic roots showed a reduction of the number of macrophages in intima. Additional in-vitro experiments revealed reduction of monocyte adhesion to endothelial cells, as well as modulation in expression of atherogenesis-related genes, when cells were pre-exposed to polyphenol metabolites at physiologically-relevant concentrations. To deepen molecular mechanisms of polyphenols, we investigated the impact of plasma metabolites of polyphenols on cell signaling pathways and miRNA expression in endothelial cells. The nutrigenomic effect in endothelial cells was associated with modulation of the phosphorylation level of several transcription factors and signaling pathway proteins, such as p38, p65 or Akt. We also observed changes in expression of miRNA in endothelial cells and bioinformatic analysis suggests that miRNA-target genes are also involved in processes of adhesion, transendothelial migration, focal adhesion or cytoskeleton organization. The role and impact of dietary polyphenols on endothelial function and gene expression in humans was investigated. We showed that orange juice decreases diastolic blood pressure and significantly improves postprandial microvascular endothelial reactivity and that hesperidin could be causally linked to the observed beneficial effect of orange juice. Nutrigenomics study revealed that orange juice and hesperidin consumption commonly modulated expression of 1,582 genes. Many of these genes were involved in chemotaxis, adhesion, infiltration and lipid transport, which is suggestive of a lower recruitment and infiltration of circulating cells to vascular wall and lower lipid accumulation. In conclusion, these results provide both evidence for cardiovascular protective effect of polyphenols and a global integrated view of the potent mechanisms by which plasma metabolites of polyphenols works at the endothelial level
Use of nutrigenomics in understanding mechanisms underlying the vascular protective effects of dietary polyphenols
No full textPresenting author: Dragan Milenkovic The Second International Congress of Translational Research in Human Nutrition is organised by the Research Centre in Human Nutrition (CRNH) of Auvergne, of which INRA is a member, in collaboration with NuGO, European Association of universities and research institutes in the field of nutrigenomicsPresenting author: Dragan Milenkovic The Second International Congress of Translational Research in Human Nutrition is organised by the Research Centre in Human Nutrition (CRNH) of Auvergne, of which INRA is a member, in collaboration with NuGO, European Association of universities and research institutes in the field of nutrigenomicsEpidemiological, human and animal studies suggest a protective role of dietary polyphenols against cardiovascular diseases. Their capacity to modulate genes expression and signaling pathways may be involved in their cardiovascular protective effects but the mechanisms remain still unknown. The aim of our research is to investigate the cardiovascular protective property of polyphenols and decipher underlying molecular mechanisms using holistic nutrigenomics approach. In murin models of atherosclerosis, 16-week supplementation with nutritionally-relevant doses of polyphenols (catechin, bilberry anthocyanins, naringin or curcumin) decreased progression of atherosclerosis. Nutrigenomic studies of aorta indicated that polyphenols modified the expression of hundreds genes and functional analysis of these data identified a cluster of common pathways related to cell-cell adhesion, cell junctions, focal adhesion, and cell cytoskeleton. These processes regulate adhesion and transendothelial migration of monocytes into the intima of blood vessels, the initial step of atherosclerosis development. Immunofluorescence analysis of the aortic roots showed a reduction of the number of macrophages in intima. Additional in-vitro experiments revealed reduction of monocyte adhesion to endothelial cells, as well as modulation in expression of atherogenesis-related genes, when cells were pre-exposed to polyphenol metabolites at physiologically-relevant concentrations. To deepen molecular mechanisms of polyphenols, we investigated the impact of plasma metabolites of polyphenols on cell signaling pathways and miRNA expression in endothelial cells. The nutrigenomic effect in endothelial cells was associated with modulation of the phosphorylation level of several transcription factors and signaling pathway proteins, such as p38, p65 or Akt. We also observed changes in expression of miRNA in endothelial cells and bioinformatic analysis suggests that miRNA-target genes are also involved in processes of adhesion, transendothelial migration, focal adhesion or cytoskeleton organization. The role and impact of dietary polyphenols on endothelial function and gene expression in humans was investigated. We showed that orange juice decreases diastolic blood pressure and significantly improves postprandial microvascular endothelial reactivity and that hesperidin could be causally linked to the observed beneficial effect of orange juice. Nutrigenomics study revealed that orange juice and hesperidin consumption commonly modulated expression of 1,582 genes. Many of these genes were involved in chemotaxis, adhesion, infiltration and lipid transport, which is suggestive of a lower recruitment and infiltration of circulating cells to vascular wall and lower lipid accumulation. In conclusion, these results provide both evidence for cardiovascular protective effect of polyphenols and a global integrated view of the potent mechanisms by which plasma metabolites of polyphenols works at the endothelial level
E2M: A deep learning framework for associating combinatorial methylation patterns with gene expression
No full textSubmission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2021-05-01The student, Jianhao Peng, accepted the attached license on 2019-03-29 at 11:15.The student, Jianhao Peng, submitted this Thesis for approval on 2019-03-29 at 11:36.This Thesis was approved for publication on 2019-03-29 at 17:13.We focus on the new problem of determining which methylation patterns in gene promoters strongly associate with gene expression in cancer cells of different types. Although a number of results regarding the influence of methylation on expression data have been reported in the literature, our approach is unique insofar as it retrospectively predicts the combinations of methylated sites in promoter regions of genes that are reflected in the expression data. Reversing the traditional prediction order in many cases makes estimation of the model parameters easier, as real-valued data are used to predict categorical data, rather than vice-versa; in addition, our approach allows one to better assess the overall influence of methylation in modulating expression via state-of-the-art learning methods. For this purpose, we developed a novel neural network learning framework termed E2M (Expression-to- Methylation) to predict the status of different methylation sites in promoter regions of several bio-marker genes based on sufficient statistics of the whole gene expression captured through Landmark genes. We ran our experiments on unquantized and quantized expression sets and neural network weights to illustrate the robustness of the method and reduce the storage footprint of the processing pipeline.
We implemented a number of machine learning algorithms to address the new problem of methylation pattern inference, including multiclass regression, canonical correlation analysis (CCA), naive fully connected neural network and inception neural networks. Inception neural networks such as E2M learners outperform all other techniques and offer an average prediction accuracy of 82% when tested on 3, 671 pan-cancer samples including low grade glioma, glioblastoma, lung adenocarcinoma, lung squamus cell carcinoma, and stomach adenocarcinoma. As an illustrative example, one can increase the prediction accuracy for the methylation pattern in the promoter of gene GATA6 in glioblastoma samples by 20% when using inception rather than simple fully connected neural networks. These performance guarantees remain largely unchanged even when both expression values and network weights are quantized. Our work also provides new insight about the importance of specific methylation site patterns on expression variations for different genes. In this context, we identified genes for which the overwhelming majority of patients exhibit one methylation pattern, and other genes with three or more significant classes of methylation patterns. Inception networks identify such patterns with high accuracy and suggest possible stratification of cancers based on methylation pattern profiles.
The E2M code and datasets are freely available at https://github.com/jianhao2016/E2MDSpace SAF Submission Ingestion Package generated from Vireo submission #13472 on 2019-08-22 at 16:20:34Made available in DSpace on 2019-08-23T20:44:37Z (GMT). No. of bitstreams: 3
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Previous issue date: 2019-03-29Embargo set by: Seth Robbins for item 112274
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COX7A2L Is a Mitochondrial Complex III Binding Protein that Stabilizes the III2+IV Supercomplex without Affecting Respirasome Formation
No full textSummaryMitochondrial respiratory chain (MRC) complexes I, III, and IV associate into a variety of supramolecular structures known as supercomplexes and respirasomes. While COX7A2L was originally described as a supercomplex-specific factor responsible for the dynamic association of complex IV into these structures to adapt MRC function to metabolic variations, this role has been disputed. Here, we further examine the functional significance of COX7A2L in the structural organization of the mammalian respiratory chain. As in the mouse, human COX7A2L binds primarily to free mitochondrial complex III and, to a minor extent, to complex IV to specifically promote the stabilization of the III2+IV supercomplex without affecting respirasome formation. Furthermore, COX7A2L does not affect the biogenesis, stabilization, and function of the individual oxidative phosphorylation complexes. These data show that independent regulatory mechanisms for the biogenesis and turnover of different MRC supercomplex structures co-exist
Regulation of mtDNA gene expression and the role of respiratory chain supercomplexes in mammalian mitochondria
No full textMitochondria are cellular organelles found in nearly all eukaryotic cells, where they fulfill a plethora of functions, including energy conversion. They harness energy from carbon sources to synthesize adenosine triphosphate (ATP) through the process of oxidative phosphorylation (OXPHOS). Mammalian mitochondria contain ~1200 proteins and only 13 of these are encoded by mitochondrial DNA (mtDNA). Despite the small contribution to the mitochondrial proteome, expression of mtDNA is nevertheless critically important for biogenesis and normal function of the OXPHOS system. The expression of mtDNA is dependent on ~200 nucleus-encoded proteins that are imported into mitochondria to control maintenance, replication, and transcription of mtDNA, as well as translation of the mtDNA-encoded messenger RNAs (mRNAs). Mitochondrial gene expression is thus controlled at many different levels. In the first part of this thesis, molecular mechanisms are reported for initiation and completion of mtDNA replication. Furthermore, mechanisms controlling the switch from transcription initiation to elongation, as well as a putative link between transcription elongation and RNA processing are reported. These results were based on extensive analysis of conditional knockout mouse models for RNase H1, TEFM, and mtSSB. In the second part of the thesis, the organization of the OXPHOS system is studied. It consists of the respiratory chain enzyme complexes, two electron shuttles and the ATP synthase. A wide range of studies have shown that the different respiratory chain enzyme complexes can interact with each other to form higher order assemblies, so called supercomplexes. The respirasome is a particularly interesting supercomplex as it consists of a complete respiratory chain. Results from multiple studies have suggested that the respirasome plays a crucial role in cellular bioenergetics by facilitating translocation and routing of electrons. To address this question, we extensively characterized a knockin mouse model engineered to have normal levels of respiratory chain complexes that cannot interact to form respirasomes. Surprisingly, mice with drastically reduced levels of respirasomes are healthy without any clear impact on bioenergetics or whole animal physiology. Our results thus challenge the multiple proposed roles for respirasomes in physiology and disease.List of scientific papersI. Jelena Misic, Dusanka Milenkovic, Ali Al-Behadili, Xie Xie, Min Jiang, Shan Jiang, Roberta Filograna, Camilla Koolmeister, Stefan J. Siira, Louise Jenninger, Aleksandra Filipovska, Anders R. Clausen, Leonardo Caporali, Maria Lucia Valentino, Chiara La Morgia, Valerio Carelli, Thomas J. Nicholls, Anna Wredenberg, Maria Falkenberg, Nils-Göran Larsson†. (2022). Mammalian RNase H1 directs RNA primer formation for mtDNA replication initiation and is also necessary for mtDNA replication completion. Nucleic Acids Res. 50, 8749–8766. †Corresponding author(s). https://doi.org/10.1093/nar/gkac661 II. Shan Jiang, Camilla Koolmeister, Jelena Misic, Stefan Siira, Inge Kühl, Eduardo Silva Ramos, Maria Miranda, Min Jiang, Viktor Posse, Oleksandr Lytovchenko, Ilian Atanassov, Florian A. Schober, Rolf Wibom, Kjell Hultenby, Dusanka Milenkovic, Claes M. Gustafsson, Aleksandra Filipovska, Nils-Göran Larsson†. (2019). TEFM regulates both transcription elongation and RNA processing in mitochondria. EMBO Rep. 20, 1–18. †Corresponding author(s). https://doi.org/10.15252/embr.201948101 III. Min Jiang*, Xie Xie*, Xuefeng Zhu*, Shan Jiang, Dusanka Milenkovic, Jelena Misic, Yonghong Shi, Nirwan Tandukar, Xinping Li, Ilian Atanassov, Louise Jenninger, Emily Hoberg, Sara Albarran-Gutierrez, Zsolt Szilagyi, Bertil Macao, Stefan J. Siira, Valerio Carelli, Jack D. Griffith, Claes M. Gustafsson, Thomas J. Nicholls, Aleksandra Filipovska, Nils-Göran Larsson†, Maria Falkenberg†. (2021). The mitochondrial single-stranded DNA binding protein is essential for initiation of mtDNA replication. Sci Adv. 7, eabf8631. *These authors contributed equally. †Corresponding author(s). https://doi.org/10.1126/sciadv.abf8631 IV. Dusanka Milenkovic, Jelena Misic, Johannes F. Hevler, Thibaut Molinié, Injae Chung, Ilian Atanassov, Xinping Li, Roberta Filograna, Andrea Mesaros, Arnaud Mourier, Albert J.R. Heck, Judy Hirst†, Nils-Göran Larsson†. (2023). Preserved respiratory chain capacity and physiology in mice with profoundly reduced levels of mitochondrial respirasomes. Cell Metab. 35, 1799-1813.e7. †Corresponding author(s). https://doi.org/10.1016/j.cmet.2023.07.015 </p
Music and crisis
No full textIn this article the author does not consider crisis a threat, but in a modern
sense, an auto-motive drive of art. Therefore, crisis does not affect the
art from the outside, it does not hit it as an illness or a storm, but it
always produces itself, which is considered to be a condition for movement
in art. First of all, the author analyzes the notion of representation and
the four roots of the sufficient reason as a conservative and conserving
element of art, to which he opposes crisis and its self-production as
something that resists sclerotization of art forms. In music, the relation
between the ossified, "naturalized" structure and that which decomposes that
structure, manifests itself as the relation between harmony and disharmony.
The moment when harmony shows a tendency towards naturality, understanding
eternity and truth, an alarm is activated to show that music is being
paralyzed and it needs a deconstructive intervention of disharmony,
atonality and dissonance
Long-memory stochastic volatility model calibration using deep neural nets
No full textWidespread use of stochastic volatility models in the financial industry is bottlenecked by the complexity and intractability they present. Since the seminal work in quantitative finance by Black et al. and Merton, the infamous Black-Scholes model has been extensively used in the industry for vanilla and exotic option pricing. Although the model assumes constant volatility which is not observed in the market, the widespread use is sustained due to its closed-form solution for European vanilla option.
However, with the advent of neural networks, stochastic volatility models are becoming increasing tractable. The use of neural networks to learn the expectation function of the underlying stochastic volatility processes for calibration makes application of these more involved stochastic volatility models in the industrial settings practical. This thesis extends this application of neural networks to the calibration of long-memory stochastic volatility (LMSV) models, a class of stochastic volatility models characterized by fractional Brownian motion. The specific challenge with these long-memory models is that they are non-Markovian in nature and simulation can be time-consuming and costly. We show that by using neural networks we can capture these non-Markovian characteristics and quickly calibrate them to ever-evolving market conditions despite their high computational cost.Submission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2023-05-01The student, Ahnaf Masroor, accepted the attached license on 2021-04-29 at 13:27.The student, Ahnaf Masroor, submitted this Thesis for approval on 2021-04-29 at 13:40.This Thesis was approved for publication on 2021-04-29 at 15:14.DSpace SAF Submission Ingestion Package generated from Vireo submission #15881 on 2021-09-16 at 17:01:25Made available in DSpace on 2021-09-17T02:34:09Z (GMT). No. of bitstreams: 2
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Previous issue date: 2021-04-29Embargo set by: Seth Robbins for item 118457
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Reason: Author requested U of Illinois access only (OA after 2yrs) in Vireo ETD systemAuthor requested U of Illinois access only (OA after 2yrs) in Vireo ETD systemU of I Onl
Theoretical and experimental analysis of dynamic processes of pipe branch for supply water to the Pelton turbine
No full text
The Legal Issues of Franchising Agreement in Serbia - Enacting the Disclosure Law or Not
No full textIn this paper the author deals with the legal environment for franchising
in Serbia which legislation does not provide specific or explicit
provisions dealing with the franchise contract. Despite the fact that
franchising continues to grow as a preferred legal instrument to conduct business in the global market business practice in Serbia hasn’t
many experiences with franchising. The franchising agreement feature
is that arrangement which embraces elements of several types of contracts
as well as it is connected with several kinds of law which elements
qualified this contract as a contract sui generis. Except the rules regulating
commercial contracts which are in Serbia contend in the Law
of Obligations (based on the Suisse Law of Obligations) and the law
of intellectual property rights which is in Serbia harmonized with the
main principles of European intellectual property rights there are significant
different branches of law which are essentially connected with
franchising. Except the rules of general contract law which in Serbia
regulate in the same way commercial and non commercial contracts,
there are specific Law on Financial Leasing (2003). Law on Business
Entities, taxation law, property law, Law on Consumer Protection and
Law on Productor’s Liability, The Investment Law, Competition Law
and other different areas of law the majority of which are regulated
domestically and at the times domestically. At the international level
franchising is object of harmonious regulation enacted in UNIDROIT
Guide on International Master Franchise Arrangements and Franchising
Disclosure Model Law created in 2002 by the experts under auspices
of UNIDROIT. Experiences of number of countries manifested that
it is necessary to enact the specific disclosure regulation over franchising
in order to protect the economically weaker party in franchising
contract - franchisee. Proposal of the author of the article is prompt
translation of the UNIDROIT Legal Guide on Franchising and de lege
ferenda enacting specific legislation in Serbia which will deal only with
the question of disclosure commitment in franchising contract
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