Chapter 15. The Impact of Genomics, Systems Biology, and Bioinformatics on Drug and Target Discovery: Challenge and Opportunity

Author(s):  
Darren R. Flower
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Rameen Shakur ◽  
Juan Pablo Ochoa ◽  
Alan J. Robinson ◽  
Abhishek Niroula ◽  
Aneesh Chandran ◽  
...  

AbstractThe cardiac troponin T variations have often been used as an example of the application of clinical genotyping for prognostication and risk stratification measures for the management of patients with a family history of sudden cardiac death or familial cardiomyopathy. Given the disparity in patient outcomes and therapy options, we investigated the impact of variations on the intermolecular interactions across the thin filament complex as an example of an unbiased systems biology method to better define clinical prognosis to aid future management options. We present a novel unbiased dynamic model to define and analyse the functional, structural and physico-chemical consequences of genetic variations among the troponins. This was subsequently integrated with clinical data from accessible global multi-centre systematic reviews of familial cardiomyopathy cases from 106 articles of the literature: 136 disease-causing variations pertaining to 981 global clinical cases. Troponin T variations showed distinct pathogenic hotspots for dilated and hypertrophic cardiomyopathies; considering the causes of cardiovascular death separately, there was a worse survival in terms of sudden cardiac death for patients with a variation at regions 90–129 and 130–179 when compared to amino acids 1–89 and 200–288. Our data support variations among 90–130 as being a hotspot for sudden cardiac death and the region 131–179 for heart failure death/transplantation outcomes wherein the most common phenotype was dilated cardiomyopathy. Survival analysis into regions of high risk (regions 90–129 and 130–180) and low risk (regions 1–89 and 200–288) was significant for sudden cardiac death (p = 0.011) and for heart failure death/transplant (p = 0.028). Our integrative genomic, structural, model from genotype to clinical data integration has implications for enhancing clinical genomics methodologies to improve risk stratification.


2015 ◽  
Vol 14 ◽  
pp. CIN.S34144 ◽  
Author(s):  
Afshin Beheshti ◽  
Donna Neuberg ◽  
J. Tyson Mcdonald ◽  
Charles R. Vanderburg ◽  
Andrew M. Evens

Potential molecular alterations based on age and sex are not well defined in diffuse large B-cell lymphoma (DLBCL). We examined global transcriptome DLBCL data from The Cancer Genome Atlas (TCGA) via a systems biology approach to determine the molecular differences associated with age and sex. Collectively, sex and age revealed striking transcriptional differences with older age associated with decreased metabolism and telomere functions and female sex was associated with decreased interferon signaling, transcription, cell cycle, and PD-1 signaling. We discovered that the key genes for most groups strongly regulated immune function activity. Furthermore, older females were predicted to have less DLBCL progression versus older males and young females. Finally, analyses in systems biology revealed that JUN and CYCS signaling were the most critical factors associated with tumor progression in older and male patients. We identified important molecular perturbations in DLBCL that were strongly associated with age and sex and were predicted to strongly influence tumor progression.


2017 ◽  
Vol 35 (12) ◽  
pp. 1156-1168 ◽  
Author(s):  
Kate Campbell ◽  
Jianye Xia ◽  
Jens Nielsen
Keyword(s):  

2010 ◽  
Vol 5 (5) ◽  
pp. 425-439 ◽  
Author(s):  
Tianxiao Huan ◽  
Xiaogang Wu ◽  
Jake Y Chen

Author(s):  
Songül Yaşar Yıldız

Glycobiology is a glycan-based field of study that focuses on the structure, function, and biology of carbohydrates, and glycomics is a sub-study of the field of glycobiology that aims to define structure/function of glycans in living organisms. With the popularity of the glycobiology and glycomics, application of computational modeling expanded in the scientific area of glycobiology over the last decades. The recent availability of progressive Wet-Lab methods in the field of glycobiology and glycomics is promising for the impact of systems biology on the research area of the glycome, an emerging field that is termed “systems glycobiology.” This chapter will summarize the up-to-date leading edge in the use of bioinformatics tools in the field of glycobiology. The chapter provides basic knowledge both for glycobiologists interested in the application of bioinformatics tools and scientists of computational biology interested in studying the glycome.


2020 ◽  
Author(s):  
Philipp Städter ◽  
Yannik Schälte ◽  
Leonard Schmiester ◽  
Jan Hasenauer ◽  
Paul L. Stapor

AbstractOrdinary differential equation (ODE) models are a key tool to understand complex mechanisms in systems biology. These models are studied using various approaches, including stability and bifurcation analysis, but most frequently by numerical simulations. The number of required simulations is often large, e.g., when unknown parameters need to be inferred. This renders efficient and reliable numerical integration methods essential. However, these methods depend on various hyperparameters, which strongly impact the ODE solution. Despite this, and although hundreds of published ODE models are freely available in public databases, a thorough study that quantifies the impact of hyperparameters on the ODE solver in terms of accuracy and computation time is still missing. In this manuscript, we investigate which choices of algorithms and hyperparameters are generally favorable when dealing with ODE models arising from biological processes. To ensure a representative evaluation, we considered 167 published models. Our study provides evidence that most ODEs in computational biology are stiff, and we give guidelines for the choice of algorithms and hyperparameters. We anticipate that our results will help researchers in systems biology to choose appropriate numerical methods when dealing with ODE models.


2019 ◽  
Vol 12 ◽  
pp. 251686571986968
Author(s):  
Sriram Chandrasekaran

Histone modifications represent an innate cellular mechanism to link nutritional status to gene expression. Metabolites such as acetyl-CoA and S-adenosyl methionine influence gene expression by serving as substrates for modification of histones. Yet, we lack a predictive model for determining histone modification levels based on cellular metabolic state. The numerous metabolic pathways that intersect with histone marks makes it highly challenging to understand their interdependencies. Here, we highlight new systems biology tools to unravel the impact of nutritional cues and metabolic fluxes on histone modifications.


2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Guillaume Quang N’guyen ◽  
Nathalie Martin ◽  
Mani Jain ◽  
Luc Lagacé ◽  
Christian R. Landry ◽  
...  

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