Combining kinetic orders for efficient S-System modelling of gene regulatory network
- Gill, Jaskaran, Chetty, Madhu, Shatte, Adrian, Hallinan, Jennifer
- Authors: Gill, Jaskaran , Chetty, Madhu , Shatte, Adrian , Hallinan, Jennifer
- Date: 2022
- Type: Text , Journal article
- Relation: BioSystems Vol. 220, no. (2022), p.
- Full Text: false
- Reviewed:
- Description: S-System models, non-linear differential equation models, are widely used for reconstructing gene regulatory networks from temporal gene expression data. An S-System model involves two states, generation and degeneration, and uses the kinetic parameters gij and hij, to represent the direction, nature, and intensity of the genetic interactions. The need for learning a large number of model parameters results in increased computational expense. Previously, we improved the performance of the algorithm using dynamic allocation of the maximum in-degree for each gene. While the method was effective for smaller networks, a large amount of computation was still needed for larger networks. This problem arose mainly due to the increased occurrence of invalid networks during optimization, primarily because the two kinetic parameters (gij and hij) of the S-System model converge independently during optimization. Being independent, these two parameters can converge to values that can indicate contradictory gene interactions, specifically inhibition or activation. In this study, to address this major challenge in S-System modelling, we developed a novel method that includes two features: a penalty term that penalizes those networks with invalid kinetic orders, and a parameter, wij, derived by combining the kinetic parameters gij and hij. The novel penalty term was used for candidate selection during the process of optimizing the DRNI (Dynamically Regulated Network Initialization) algorithm. Rather than remaining constant, it is dynamic, with its magnitude dependent on the number of invalid interactions in the given network. This approach encourages the generation of valid candidate solutions, and eliminates invalid networks in a systematic manner. The previous DRNI method, a two-stage approach which uses dynamic allocation of the maximum in-degree for each gene, was further improved by adding a third stage which applies the proposed wij to handle the invalid regulations that may still exist in that candidate solutions. The method was tested on different gene expression datasets, and was able to reduce the number of iterations and produce improved network accuracies. For a 20 gene network, the number of generations required for convergence was reduced by 300, and the F-score improved by 0.05 compared to our previously reported DRNI approach. For the well-known 10 gene networks of the DREAM challenge, our method produced an improvement in the average area under the ROC curve of the DREAM4 10 gene networks. © 2022
Experimental and human evidence for Lipocalin-2 (Neutrophil Gelatinase-Associated Lipocalin NGAL ) in the development of cardiac hypertrophy and heart failure
- Marques, Francine, Prestes, Priscilla, Byars, Sean, Ritchie, Scott, Wurtz, Peter, Patel, Sheila, Booth, Scott, Rana, Indrajeetsinh, Minoda, Yosuke, Berzins, Stuart, Curl, Claire, Bell, James, Wai, Bryan, Srivastava, Piyush, Kangas, Antti, Soininen, Pasi, Ruohonen, Saku, Kahonen, Mika, Lehtimaki, Terho, Raitoharju, Emma, Havulinna, Aki, Perola, Markus, Raitakari, Olli, Salomaa, Veikko, Ala-Korpela, Mika, Kettunen, Johannes, McGlynn, Maree, Kelly, Jason, Wlodek, Mary, Lewandowski, Paul, Delbridge, Lea, Burrell, Louise, Inouye, Michael, Harrap, Stephen, Charchar, Fadi
- Authors: Marques, Francine , Prestes, Priscilla , Byars, Sean , Ritchie, Scott , Wurtz, Peter , Patel, Sheila , Booth, Scott , Rana, Indrajeetsinh , Minoda, Yosuke , Berzins, Stuart , Curl, Claire , Bell, James , Wai, Bryan , Srivastava, Piyush , Kangas, Antti , Soininen, Pasi , Ruohonen, Saku , Kahonen, Mika , Lehtimaki, Terho , Raitoharju, Emma , Havulinna, Aki , Perola, Markus , Raitakari, Olli , Salomaa, Veikko , Ala-Korpela, Mika , Kettunen, Johannes , McGlynn, Maree , Kelly, Jason , Wlodek, Mary , Lewandowski, Paul , Delbridge, Lea , Burrell, Louise , Inouye, Michael , Harrap, Stephen , Charchar, Fadi
- Date: 2017
- Type: Text , Journal article
- Relation: Journal of the American Heart Association Vol. 6, no. 6 (2017), p. 1-58
- Relation: http://purl.org/au-research/grants/nhmrc/1034371
- Full Text:
- Reviewed:
- Description: Background-Cardiac hypertrophy increases the risk of developing heart failure and cardiovascular death. The neutrophil inflammatory protein, lipocalin-2 (LCN2/NGAL), is elevated in certain forms of cardiac hypertrophy and acute heart failure. However, a specific role for LCN2 in predisposition and etiology of hypertrophy and the relevant genetic determinants are unclear. Here, we defined the role of LCN2 in concentric cardiac hypertrophy in terms of pathophysiology, inflammatory expression networks, and genomic determinants. Methods and Results-We used 3 experimental models: a polygenic model of cardiac hypertrophy and heart failure, a model of intrauterine growth restriction and Lcn2-knockout mouse; cultured cardiomyocytes; and 2 human cohorts: 114 type 2 diabetes mellitus patients and 2064 healthy subjects of the YFS (Young Finns Study). In hypertrophic heart rats, cardiac and circulating Lcn2 was significantly overexpressed before, during, and after development of cardiac hypertrophy and heart failure. Lcn2 expression was increased in hypertrophic hearts in a model of intrauterine growth restriction, whereas Lcn2-knockout mice had smaller hearts. In cultured cardiomyocytes, Lcn2 activated molecular hypertrophic pathways and increased cell size, but reduced proliferation and cell numbers. Increased LCN2 was associated with cardiac hypertrophy and diastolic dysfunction in diabetes mellitus. In the YFS, LCN2 expression was associated with body mass index and cardiac mass and with levels of inflammatory markers. The single-nucleotide polymorphism, rs13297295, located near LCN2 defined a significant cis-eQTL for LCN2 expression. Conclusions-Direct effects of LCN2 on cardiomyocyte size and number and the consistent associations in experimental and human analyses reveal a central role for LCN2 in the ontogeny of cardiac hypertrophy and heart failure.
- Authors: Marques, Francine , Prestes, Priscilla , Byars, Sean , Ritchie, Scott , Wurtz, Peter , Patel, Sheila , Booth, Scott , Rana, Indrajeetsinh , Minoda, Yosuke , Berzins, Stuart , Curl, Claire , Bell, James , Wai, Bryan , Srivastava, Piyush , Kangas, Antti , Soininen, Pasi , Ruohonen, Saku , Kahonen, Mika , Lehtimaki, Terho , Raitoharju, Emma , Havulinna, Aki , Perola, Markus , Raitakari, Olli , Salomaa, Veikko , Ala-Korpela, Mika , Kettunen, Johannes , McGlynn, Maree , Kelly, Jason , Wlodek, Mary , Lewandowski, Paul , Delbridge, Lea , Burrell, Louise , Inouye, Michael , Harrap, Stephen , Charchar, Fadi
- Date: 2017
- Type: Text , Journal article
- Relation: Journal of the American Heart Association Vol. 6, no. 6 (2017), p. 1-58
- Relation: http://purl.org/au-research/grants/nhmrc/1034371
- Full Text:
- Reviewed:
- Description: Background-Cardiac hypertrophy increases the risk of developing heart failure and cardiovascular death. The neutrophil inflammatory protein, lipocalin-2 (LCN2/NGAL), is elevated in certain forms of cardiac hypertrophy and acute heart failure. However, a specific role for LCN2 in predisposition and etiology of hypertrophy and the relevant genetic determinants are unclear. Here, we defined the role of LCN2 in concentric cardiac hypertrophy in terms of pathophysiology, inflammatory expression networks, and genomic determinants. Methods and Results-We used 3 experimental models: a polygenic model of cardiac hypertrophy and heart failure, a model of intrauterine growth restriction and Lcn2-knockout mouse; cultured cardiomyocytes; and 2 human cohorts: 114 type 2 diabetes mellitus patients and 2064 healthy subjects of the YFS (Young Finns Study). In hypertrophic heart rats, cardiac and circulating Lcn2 was significantly overexpressed before, during, and after development of cardiac hypertrophy and heart failure. Lcn2 expression was increased in hypertrophic hearts in a model of intrauterine growth restriction, whereas Lcn2-knockout mice had smaller hearts. In cultured cardiomyocytes, Lcn2 activated molecular hypertrophic pathways and increased cell size, but reduced proliferation and cell numbers. Increased LCN2 was associated with cardiac hypertrophy and diastolic dysfunction in diabetes mellitus. In the YFS, LCN2 expression was associated with body mass index and cardiac mass and with levels of inflammatory markers. The single-nucleotide polymorphism, rs13297295, located near LCN2 defined a significant cis-eQTL for LCN2 expression. Conclusions-Direct effects of LCN2 on cardiomyocyte size and number and the consistent associations in experimental and human analyses reveal a central role for LCN2 in the ontogeny of cardiac hypertrophy and heart failure.
A roadmap to generate renewable protein binders to the human proteome
- Colwill, Karen, Persson, Helena, Jarvik, Nicholas, Wyrzucki, Arkadiusz, Wojcik, John, Koide, Akiko, Kossiakoff, Anthony, Koide, Shohei, Sidhu, Sachdev, Dyson, Michael, Pershad, Kritika, Pavlovic, John, Karatt-Vellatt, Aneesh, Schofield, Darren, Kay, Brian, McCafferty, John, Mersmann, Michael, Meier, Doris, Mersmann, Jana, Helmsing, Saskia, Hust, Michael, Dubel, Stefan, Berkowicz, Susan, Freemantle, Alexia, Spiegel, Michael, Sawyer, Alan, Layton, Daniel, Nice, Edouard, Dai, Anna, Rocks, Oliver, Williton, Kelly, Fellouse, Frederic, Hersi, Kadija, Pawson, Tony, Nilsson, Peter, Sundberg, Marten, Sjoberg, Ronald, Sivertsson, Asa, Schwenk, Jochen, Takanen, Jenny, Hober, Sophia, Uhlen, Mathias, Dahlgren, Lars-Goran, Flores, Alex, Johansson, Ida, Weigelt, Johan, Crombet, Lissette, Loppnau, Peter, Kozieradzki, Ivona, Cossar, Doug, Arrowsmith, C., Edwards, Aled, Graslund, Susanne
- Authors: Colwill, Karen , Persson, Helena , Jarvik, Nicholas , Wyrzucki, Arkadiusz , Wojcik, John , Koide, Akiko , Kossiakoff, Anthony , Koide, Shohei , Sidhu, Sachdev , Dyson, Michael , Pershad, Kritika , Pavlovic, John , Karatt-Vellatt, Aneesh , Schofield, Darren , Kay, Brian , McCafferty, John , Mersmann, Michael , Meier, Doris , Mersmann, Jana , Helmsing, Saskia , Hust, Michael , Dubel, Stefan , Berkowicz, Susan , Freemantle, Alexia , Spiegel, Michael , Sawyer, Alan , Layton, Daniel , Nice, Edouard , Dai, Anna , Rocks, Oliver , Williton, Kelly , Fellouse, Frederic , Hersi, Kadija , Pawson, Tony , Nilsson, Peter , Sundberg, Marten , Sjoberg, Ronald , Sivertsson, Asa , Schwenk, Jochen , Takanen, Jenny , Hober, Sophia , Uhlen, Mathias , Dahlgren, Lars-Goran , Flores, Alex , Johansson, Ida , Weigelt, Johan , Crombet, Lissette , Loppnau, Peter , Kozieradzki, Ivona , Cossar, Doug , Arrowsmith, C. , Edwards, Aled , Graslund, Susanne
- Date: 2011
- Type: Text , Journal article
- Relation: Nature Methods Vol. 8, no. 7 (2011), p. 551-558
- Full Text: false
- Reviewed:
- Description: Despite the wealth of commercially available antibodies to human proteins, research is often hindered by their inconsistent validation, their poor performance and the inadequate coverage of the proteome. These issues could be addressed by systematic, genome-wide efforts to generate and validate renewable protein binders. We report a multicenter study to assess the potential of hybridoma and phage-display technologies in a coordinated large-scale antibody generation and validation effort. We produced over 1,000 antibodies targeting 20 SH2 domain proteins and evaluated them for potency and specificity by enzyme-linked immunosorbent assay (ELISA), protein microarray and surface plasmon resonance (SPR). We also tested selected antibodies in immunoprecipitation, immunoblotting and immunofluorescence assays. Our results show that high-affinity, high-specificity renewable antibodies generated by different technologies can be produced quickly and efficiently. We believe that this work serves as a foundation and template for future larger-scale studies to create renewable protein binders.
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