93 research outputs found
Inferring Pattern and Disorder in Close-Packed Structures from X-ray Diffraction Studies, Part II: Structure and Intrinsic Computation in Zinc Sulphide
In the previous paper of this series [D. P. Varn, G. S. Canright, and J. P.
Crutchfield, Physical Review B, submitted] we detailed a
procedure--epsilon-machine spectral reconstruction--to discover and analyze
patterns and disorder in close-packed structures as revealed in x-ray
diffraction spectra. We argued that this computational mechanics approach is
more general than the current alternative theory, the fault model, and that it
provides a unique characterization of the disorder present. We demonstrated the
efficacy of computational mechanics on four prototype spectra, finding that it
was able to recover a statistical description of the underlying modular-layer
stacking using epsilon-machine representations. Here we use this procedure to
analyze structure and disorder in four previously published zinc sulphide
diffraction spectra. We selected zinc sulphide not only for the theoretical
interest this material has attracted in an effort to develop an understanding
of polytypism, but also because it displays solid-state phase transitions and
experimental data is available.Comment: 15 pages, 14 figures, 4 tables, 57 citations;
http://www.santafe.edu/projects/CompMech/papers/ipdcpsii.htm
Inferring Pattern and Disorder in Close-Packed Structures from X-ray Diffraction Studies, Part I: epsilon-Machine Spectral Reconstruction Theory
In a recent publication [D. P. Varn, G. S. Canright, and J. P. Crutchfield,
Phys. Rev. B {\bf 66}:17, 156 (2002)] we introduced a new technique for
discovering and describing planar disorder in close-packed structures (CPSs)
directly from their diffraction spectra. Here we provide the theoretical
development behind those results, adapting computational mechanics to describe
one-dimensional structure in materials. By way of contrast, we give a detailed
analysis of the current alternative approach, the fault model (FM), and offer
several criticisms. We then demonstrate that the computational mechanics
description of the stacking sequence--in the form of an
epsilon-machine--provides the minimal and unique description of the crystal,
whether ordered, disordered, or some combination. We find that we can detect
and describe any amount of disorder, as well as materials that are mixtures of
various kinds of crystalline structure. Underlying this approach is a novel
method for epsilon-machine reconstruction that uses correlation functions
estimated from diffraction spectra, rather than sequences of microscopic
configurations, as is typically used in other domains. The result is that the
methods developed here can be adapted to a wide range of experimental systems
in which spectroscopic data is available.Comment: 26 pages, 23 figures, 8 tables, 110 citations;
http://www.santafe.edu/projects/CompMech/papers/ipdcpsi.htm
Systematic Analysis of Hematopoietic Gene Expression Profiles for Prognostic Prediction in Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is a hematopoietic disorder initiated by the leukemogenic transformation of myeloid cells into leukemia stem cells (LSCs). Preexisting gene expression programs in LSCs can be used to assess their transcriptional similarity to hematopoietic cell types. While this relationship has previously been examined on a small scale, an analysis that systematically investigates this relationship throughout the hematopoietic hierarchy has yet to be implemented. We developed an integrative approach to assess the similarity between AML patient tumor profiles and a collection of 232 murine hematopoietic gene expression profiles compiled by the Immunological Genome Project. The resulting lineage similarity scores (LSS) were correlated with patient survival to assess the relationship between hematopoietic similarity and patient prognosis. This analysis demonstrated that patient tumor similarity to immature hematopoietic cell types correlated with poor survival. As a proof of concept, we highlighted one cell type identified by our analysis, the short-term reconstituting stem cell, whose LSSs were significantly correlated with patient prognosis across multiple datasets, and showed distinct patterns in patients stratified by traditional clinical variables. Finally, we validated our use of murine profiles by demonstrating similar results when applying our method to human profiles
Regulators Associated with Clinical Outcomes Revealed by Dna Methylation Data in Breast Cancer
The regulatory architecture of breast cancer is extraordinarily complex and gene misregulation can occur at many levels, with transcriptional malfunction being a major cause. This dysfunctional process typically involves additional regulatory modulators including DNA methylation. Thus, the interplay between transcription factor (TF) binding and DNA methylation are two components of a cancer regulatory interactome presumed to display correlated signals. As proof of concept, we performed a systematic motif-based in silico analysis to infer all potential TFs that are involved in breast cancer prognosis through an association with DNA methylation changes. Using breast cancer DNA methylation and clinical data derived from The Cancer Genome Atlas (TCGA), we carried out a systematic inference of TFs whose misregulation underlie different clinical subtypes of breast cancer. Our analysis identified TFs known to be associated with clinical outcomes of p53 and ER (estrogen receptor) subtypes of breast cancer, while also predicting new TFs that may also be involved. Furthermore, our results suggest that misregulation in breast cancer can be caused by the binding of alternative factors to the binding sites of TFs whose activity has been ablated. Overall, this study provides a comprehensive analysis that links DNA methylation to TF binding to patient prognosis
Integrative Analysis of Survival-Associated Gene Sets in Breast Cancer
Patient gene expression information has recently become a clinical feature used to evaluate breast cancer prognosis. The emergence of prognostic gene sets that take advantage of these data has led to a rich library of information that can be used to characterize the molecular nature of a patientās cancer. Identifying robust gene sets that are consistently predictive of a patientās clinical outcome has become one of the main challenges in the field. We inputted our previously established BASE algorithm with patient gene expression data and gene sets from MSigDB to develop the gene set activity score (GSAS), a metric that quantitatively assesses a gene setās activity level in a given patient. We utilized this metric, along with patient time-to-event data, to perform survival analyses to identify the gene sets that were significantly correlated with patient survival. We then performed cross-dataset analyses to identify robust prognostic gene sets and to classify patients by metastasis status. Additionally, we created a gene set network based on component gene overlap to explore the relationship between gene sets derived from MSigDB. We developed a novel gene set based on this networkās topology and applied the GSAS metric to characterize its role in patient survival
Exact Synchronization for Finite-State Sources
We analyze how an observer synchronizes to the internal state of a
finite-state information source, using the epsilon-machine causal
representation. Here, we treat the case of exact synchronization, when it is
possible for the observer to synchronize completely after a finite number of
observations. The more difficult case of strictly asymptotic synchronization is
treated in a sequel. In both cases, we find that an observer, on average, will
synchronize to the source state exponentially fast and that, as a result, the
average accuracy in an observer's predictions of the source output approaches
its optimal level exponentially fast as well. Additionally, we show here how to
analytically calculate the synchronization rate for exact epsilon-machines and
provide an efficient polynomial-time algorithm to test epsilon-machines for
exactness.Comment: 9 pages, 6 figures; now includes analytical calculation of the
synchronization rate; updates and corrections adde
Integrative Analysis of Breast Cancer Reveals Prognostic Haematopoietic Activity and Patient-Specific Immune Response Profiles
Transcriptional programmes active in haematopoietic cells enable a variety of functions including dedifferentiation, innate immunity and adaptive immunity. Understanding how these programmes function in the context of cancer can provide valuable insights into host immune response, cancer severity and potential therapy response. Here we present a method that uses the transcriptomes of over 200 murine haematopoietic cells, to infer the lineage-specific haematopoietic activity present in human breast tumours. Correlating this activity with patient survival and tumour purity reveals that the transcriptional programmes of many cell types influence patient prognosis and are found in environments of high lymphocytic infiltration. Collectively, these results allow for a detailed and personalized assessment of the patient immune response to a tumour. When combined with routinely collected patient biopsy genomic data, this method can enable a richer understanding of the complex interplay between the host immune system and cancer
Honesty mediates the relationship between serotonin and reaction to unfairness
How does one deal with unfair behaviors? This subject has long been investigated by various disciplines including philosophy, psychology, economics, and biology. However, our reactions to unfairness differ from one individual to another. Experimental economics studies using the ultimatum game (UG), in which players must decide whether to accept or reject fair or unfair offers, have also shown that there are substantial individual differences in reaction to unfairness. However, little is known about psychological as well as neurobiological mechanisms of this observation. We combined a molecular imaging technique, an economics game, and a personality inventory to elucidate the neurobiological mechanism of heterogeneous reactions to unfairness. Contrary to the common belief that aggressive personalities (impulsivity or hostility) are related to the high rejection rate of unfair offers in UG, we found that individuals with apparently peaceful personalities (straightforwardness and trust) rejected more often and were engaged in personally costly forms of retaliation. Furthermore, individuals with a low level of serotonin transporters in the dorsal raphe nucleus (DRN) are honest and trustful, and thus cannot tolerate unfairness, being candid in expressing their frustrations. In other words, higher central serotonin transmission might allow us to behave adroitly and opportunistically, being good at playing games while pursuing self-interest. We provide unique neurobiological evidence to account for individual differences of reaction to unfairness
Perspective of mesenchymal transformation in glioblastoma.
Despite aggressive multimodal treatment, glioblastoma (GBM), a grade IV primary brain tumor, still portends a poor prognosis with a median overall survival of 12-16 months. The complexity of GBM treatment mainly lies in the inter- and intra-tumoral heterogeneity, which largely contributes to the treatment-refractory and recurrent nature of GBM. By paving the road towards the development of personalized medicine for GBM patients, the cancer genome atlas classification scheme of GBM into distinct transcriptional subtypes has been considered an invaluable approach to overcoming this heterogeneity. Among the identified transcriptional subtypes, the mesenchymal subtype has been found associated with more aggressive, invasive, angiogenic, hypoxic, necrotic, inflammatory, and multitherapy-resistant features than other transcriptional subtypes. Accordingly, mesenchymal GBM patients were found to exhibit worse prognosis than other subtypes when patients with high transcriptional heterogeneity were excluded. Furthermore, identification of the master mesenchymal regulators and their downstream signaling pathways has not only increased our understanding of the complex regulatory transcriptional networks of mesenchymal GBM, but also has generated a list of potent inhibitors for clinical trials. Importantly, the mesenchymal transition of GBM has been found to be tightly associated with treatment-induced phenotypic changes in recurrence. Together, these findings indicate that elucidating the governing and plastic transcriptomic natures of mesenchymal GBM is critical in order to develop novel and selective therapeutic strategies that can improve both patient care and clinical outcomes. Thus, the focus of our review will be on the recent advances in the understanding of the transcriptome of mesenchymal GBM and discuss microenvironmental, metabolic, and treatment-related factors as critical components through which the mesenchymal signature may be acquired. We also take into consideration the transcriptomic plasticity of GBM to discuss the future perspectives in employing selective therapeutic strategies against mesenchymal GBM
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