Generalized logical model based on network topology to capture the dynamical trends of cellular signaling pathways

Background

Cellular responses to extracellular perturbations require signaling pathways to capture and transmit the signals. However, the underlying molecular mechanisms of signal transduction are not yet fully understood, thus detailed and comprehensive models may not be available for all the signaling pathways. In particular, insufficient knowledge of parameters, which is a long-standing hindrance for quantitative kinetic modeling necessitates the use of parameter-free methods for modeling and simulation to capture dynamic properties of signaling pathways.

Results

We present a computational model that is able to simulate the graded responses to degradations, the sigmoidal biological relationships between signaling molecules and the effects of scheduled perturbations to the cells. The simulation results are validated using experimental data of protein phosphorylation, demonstrating that the proposed model is capable of capturing the main trend of protein activities during the process of signal transduction. Compared with existing simulators, our model has better performance on predicting the state transitions of signaling networks.

Conclusion

The proposed simulation tool provides a valuable resource for modeling cellular signaling pathways using a knowledge-based method.

     

Novel extracellular and nuclear caspase-1 and inflammasomes propagate inflammation and regulate gene expression: a comprehensive database mining study

Background

Caspase-1 is present in the cytosol as an inactive zymogen and requires the protein complexes named “inflammasomes” for proteolytic activation. However, it remains unclear whether the proteolytic activity of caspase-1 is confined only to the cytosol where inflammasomes are assembled to convert inactive pro-caspase-1 to active caspase-1.

Methods

We conducted meticulous data analysis method?s on proteomic, protein interaction, protein intracellular localization, and gene expressions of 114 experimentally identified caspase-1 substrates and 38 caspase-1 interaction proteins in normal physiological conditions and in various pathologies.

Results

We made the following important findings: (1) Caspase-1 substrates and interaction proteins are localized in various intracellular organelles including nucleus and secreted extracellularly; (2) Caspase-1 may get activated in situ in the nucleus in response to intra-nuclear danger signals; (3) Caspase-1 cleaves its substrates in exocytotic secretory pathways including exosomes to propagate inflammation to neighboring and remote cells; (4) Most of caspase-1 substrates are upregulated in coronary artery disease regardless of their subcellular localization but the majority of metabolic diseases cause no significant expression changes in caspase-1 nuclear substrates; and (5) In coronary artery disease, majority of upregulated caspase-1 extracellular substrate-related pathways are involved in induction of inflammation; and in contrast, upregulated caspase-1 nuclear substrate-related pathways are more involved in regulating cell death and chromatin regulation.

Conclusions

Our identification of novel caspase-1 trafficking sites, nuclear and extracellular inflammasomes, and extracellular caspase-1-based inflammation propagation model provides a list of targets for the future development of new therapeutics to treat cardiovascular diseases, inflammatory diseases, and inflammatory cancers.

     

Analysis of genetic diversity and population structure of peanut cultivars and breeding lines from China,India and the US using simple sequence repeat markers

Cultivated peanut is grown worldwide as richsource of oil and protein. A broad genetic base is needed for cultivar improvement. The objectives of this study were to develop highly informative simple sequence repeat(SSR)markers and to assess the genetic diversity and population structure of peanut cultivars and breeding lines from different breeding programs in China, India and the US. A total of 111 SSR markers were selected for this study, resulting in a total of 472 alleles. The mean values of gene diversity and polymorphic information content(PIC) were 0.480 and 0.429, respectively.Country-wise analysis revealed that alleles per locus in three countries were similar. The mean gene diversity in the US,China and India was 0.363, 0.489 and 0.47 with an average PIC of 0.323, 0.43 and 0.412, respectively. Genetic analysis using the STRUCTURE divided these peanut lines into two populations(P_1, P_2), which was consistent with the dendrogram based on genetic distance(G_1, G_2) and the clustering of principal component analysis. The groupings were related to peanut market types and the geographic origin with a few admixtures. The results could be used by breeding programs to assess the genetic diversity of breeding materials to broaden the genetic base and for molecular genetics studies.     

Examination of the quality of various force fields and solvation models for the equilibrium simulations of GA88 and GB88

Elucidating the relationship between sequence and conformation is essential for the understanding of functions of proteins. While sharing 88 % sequence identity and differing by only seven residues, GA88 and GB88 have completely different structures and serve as ideal systems for investigating the relationship between sequence and function. Benefiting from the continuous advancement of the computational ability of modern computers, molecular dynamics (MD) simulation is now playing an increasingly important role in the study of proteins. However, the reliability of MD simulations is limited by the accuracy of the force fields and solvent model approximations. In this work, several AMBER force fields (AMBER03, AMBER99SB, AMBER12SB, AMBER14SB, AMBER96) and solvent models (TIP3P, IGB5, IGB7, IGB8) have been employed in the simulations of GA88 and GB88. The statistical results from 19 simulations show that GA88 and GB88 both adopt more compact structures than the native structures. GB88 is more stable than GA88 regardless of the force fields and solvent models utilized. Most of the simulations overestimated the salt bridge interaction. The combination of AMBER14SB force field and IGB8 solvent model shows the best overall performance in the simulations of both GA88 and GB88. AMBER03 and AMBER12SB also yield reasonable results but only in the TIP3P explicit solvent model.     

Conservation genetics of rare trees restricted to subtropical montane cloud forests in southern China: a case study from <Emphasis Type="Italic">Quercus arbutifolia</Emphasis> (Fagaceae)

Montane cloud forests (MCFs), with their isolated nature, offer excellent opportunities to study the long-term effects of habitat fragmentation and the impacts of climate change. Quercus arbutifolia is a rare oak in MCFs of southern China and Vietnam. Its isolated populations, small population size and unique ecological niche make this species vulnerable to climate change and habitat loss. In this study, we used chloroplast (cpDNA) and nuclear (ITS) DNA sequences to investigate genetic divergence patterns and demographic history of five of the six known populations of Q. arbutifolia. Considering its small population size and fragmentation, Q. arbutifolia has unexpectedly high genetic diversity. The time since the most recent common ancestor of all cpDNA haplotypes was c. 10.25 Ma, and the rapid diversification of haplotypes occurred during the Quaternary. The maximum clade credibility chronogram of cpDNA haplotypes suggests that the DM population (Daming Mountain, Guangxi province) diverged early and rapidly became isolated from other populations. The Pearl River drainage system may have been the main geographic barrier between DM and other populations since the late Miocene. ITS data suggests that population expansion occurred during the last interglacial of the Quaternary. The combined effects of pre-Quaternary and Quaternary climatic and geological changes were the main drivers to the current genetic diversity and distribution pattern of Q. arbutifolia. Because of the high between-population genetic differentiation and high within-population genetic diversity of Q. arbutifolia, conservation efforts should be implemented for all populations, but if conservation resources are limited, populations DM, YZ (Mang Mountain, Hunan province) and ZZ (Daqin Mountain, Fujian province) should have priority.