79 research outputs found
Network Archaeology: Uncovering Ancient Networks from Present-day Interactions
Often questions arise about old or extinct networks. What proteins interacted
in a long-extinct ancestor species of yeast? Who were the central players in
the Last.fm social network 3 years ago? Our ability to answer such questions
has been limited by the unavailability of past versions of networks. To
overcome these limitations, we propose several algorithms for reconstructing a
network's history of growth given only the network as it exists today and a
generative model by which the network is believed to have evolved. Our
likelihood-based method finds a probable previous state of the network by
reversing the forward growth model. This approach retains node identities so
that the history of individual nodes can be tracked. We apply these algorithms
to uncover older, non-extant biological and social networks believed to have
grown via several models, including duplication-mutation with complementarity,
forest fire, and preferential attachment. Through experiments on both synthetic
and real-world data, we find that our algorithms can estimate node arrival
times, identify anchor nodes from which new nodes copy links, and can reveal
significant features of networks that have long since disappeared.Comment: 16 pages, 10 figure
Regulation of signal duration and the statistical dynamics of kinase activation by scaffold proteins
Scaffolding proteins that direct the assembly of multiple kinases into a
spatially localized signaling complex are often essential for the maintenance
of an appropriate biological response. Although scaffolds are widely believed
to have dramatic effects on the dynamics of signal propagation, the mechanisms
that underlie these consequences are not well understood. Here, Monte Carlo
simulations of a model kinase cascade are used to investigate how the temporal
characteristics of signaling cascades can be influenced by the presence of
scaffold proteins. Specifically, we examine the effects of spatially localizing
kinase components on a scaffold on signaling dynamics. The simulations indicate
that a major effect that scaffolds exert on the dynamics of cell signaling is
to control how the activation of protein kinases is distributed over time.
Scaffolds can influence the timing of kinase activation by allowing for kinases
to become activated over a broad range of times, thus allowing for signaling at
both early and late times. Scaffold concentrations that result in optimal
signal amplitude also result in the broadest distributions of times over which
kinases are activated. These calculations provide insights into one mechanism
that describes how the duration of a signal can potentially be regulated in a
scaffold mediated protein kinase cascade. Our results illustrate another
complexity in the broad array of control properties that emerge from the
physical effects of spatially localizing components of kinase cascades on
scaffold proteins.Comment: 12 pages, 6 figure
Evolution of scaling emergence in large-scale spatial epidemic spreading
Background: Zipf's law and Heaps' law are two representatives of the scaling
concepts, which play a significant role in the study of complexity science. The
coexistence of the Zipf's law and the Heaps' law motivates different
understandings on the dependence between these two scalings, which is still
hardly been clarified.
Methodology/Principal Findings: In this article, we observe an evolution
process of the scalings: the Zipf's law and the Heaps' law are naturally shaped
to coexist at the initial time, while the crossover comes with the emergence of
their inconsistency at the larger time before reaching a stable state, where
the Heaps' law still exists with the disappearance of strict Zipf's law. Such
findings are illustrated with a scenario of large-scale spatial epidemic
spreading, and the empirical results of pandemic disease support a universal
analysis of the relation between the two laws regardless of the biological
details of disease. Employing the United States(U.S.) domestic air
transportation and demographic data to construct a metapopulation model for
simulating the pandemic spread at the U.S. country level, we uncover that the
broad heterogeneity of the infrastructure plays a key role in the evolution of
scaling emergence.
Conclusions/Significance: The analyses of large-scale spatial epidemic
spreading help understand the temporal evolution of scalings, indicating the
coexistence of the Zipf's law and the Heaps' law depends on the collective
dynamics of epidemic processes, and the heterogeneity of epidemic spread
indicates the significance of performing targeted containment strategies at the
early time of a pandemic disease.Comment: 24pages, 7figures, accepted by PLoS ON
The DAC system and associations with acute leukemias and myelodysplastic syndromes
Imbalances of histone acetyltransferase (HAT) and deacetylase activity (DAC) that result in deregulated gene expression are commonly observed in leukemias. These alterations provide the basis for novel therapeutic approaches that target the epigenetic mechanisms implicated in leukemogenesis. As the acetylation status of histones has been linked to transcriptional regulation of genes involved particularly in differentiation and apoptosis, DAC inhibitors (DACi) have attracted considerable attention for treatment of hematologic malignancies. DACi encompass a structurally diverse family of compounds that are being explored as single agents as well as in combination with chemotherapeutic drugs, small molecule inhibitors of signaling pathways and hypomethylating agents. While DACi have shown clear evidence of activity in acute myeloid leukemia, myelodysplastic syndromes and lymphoid malignancies, their precise role in treatment of these different entities remain to be elucidated. Successful development of these compounds as elements of novel targeted treatment strategies for leukemia will require that clinical studies be performed in conjunction with translational research including efforts to identify predictive biomarkers
Further phenotypic characterization of the primitive lineage− CD34+CD38−CD90+CD45RA− hematopoietic stem cell/progenitor cell sub-population isolated from cord blood, mobilized peripheral blood and patients with chronic myelogenous leukemia
The most primitive hematopoietic stem cell (HSC)/progenitor cell (PC) population reported to date is characterized as being Lin−CD34+CD38−CD90+CD45R. We have a long-standing interest in comparing the characteristics of hematopoietic progenitor cell populations enriched from normal subjects and patients with chronic myelogenous leukemia (CML). In order to investigate further purification of HSCs and for potential targetable differences between the very primitive normal and CML stem/PCs, we have phenotypically compared the normal and CML Lin−CD34+CD38−CD90+CD45RA− HSC/PC populations. The additional antigens analyzed were HLA-DR, the receptor tyrosine kinases c-kit and Tie2, the interleukin-3 cytokine receptor, CD33 and the activation antigen CD69, the latter of which was recently reported to be selectively elevated in cell lines expressing the Bcr-Abl tyrosine kinase. Notably, we found a strikingly low percentage of cells from the HSC/PC sub-population isolated from CML patients that were found to express the c-kit receptor (<1%) compared with the percentages of HSC/PCs expressing the c-kitR isolated from umbilical cord blood (50%) and mobilized peripheral blood (10%). Surprisingly, Tie2 receptor expression within the HSC/PC subset was extremely low from both normal and CML samples. Using in vivo transplantation studies, we provide evidence that HLA-DR, c-kitR, Tie2 and IL-3R may not be suitable markers for further partitioning of HSCs from the Lin−CD34+CD38−CD90+CD45RA− sub-population
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