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Spatial intratumoral heterogeneity and temporal clonal evolution in esophageal squamous cell carcinoma.
Esophageal squamous cell carcinoma (ESCC) is among the most common malignancies, but little is known about its spatial intratumoral heterogeneity (ITH) and temporal clonal evolutionary processes. To address this, we performed multiregion whole-exome sequencing on 51 tumor regions from 13 ESCC cases and multiregion global methylation profiling for 3 of these 13 cases. We found an average of 35.8% heterogeneous somatic mutations with strong evidence of ITH. Half of the driver mutations located on the branches of tumor phylogenetic trees targeted oncogenes, including PIK3CA, NFE2L2 and MTOR, among others. By contrast, the majority of truncal and clonal driver mutations occurred in tumor-suppressor genes, including TP53, KMT2D and ZNF750, among others. Interestingly, phyloepigenetic trees robustly recapitulated the topological structures of the phylogenetic trees, indicating a possible relationship between genetic and epigenetic alterations. Our integrated investigations of spatial ITH and clonal evolution provide an important molecular foundation for enhanced understanding of tumorigenesis and progression in ESCC
Computational Screening of Tip and Stalk Cell Behavior Proposes a Role for Apelin Signaling in Sprout Progression
Angiogenesis involves the formation of new blood vessels by sprouting or
splitting of existing blood vessels. During sprouting, a highly motile type of
endothelial cell, called the tip cell, migrates from the blood vessels followed
by stalk cells, an endothelial cell type that forms the body of the sprout. To
get more insight into how tip cells contribute to angiogenesis, we extended an
existing computational model of vascular network formation based on the
cellular Potts model with tip and stalk differentiation, without making a
priori assumptions about the differences between tip cells and stalk cells. To
predict potential differences, we looked for parameter values that make tip
cells (a) move to the sprout tip, and (b) change the morphology of the
angiogenic networks. The screening predicted that if tip cells respond less
effectively to an endothelial chemoattractant than stalk cells, they move to
the tips of the sprouts, which impacts the morphology of the networks. A
comparison of this model prediction with genes expressed differentially in tip
and stalk cells revealed that the endothelial chemoattractant Apelin and its
receptor APJ may match the model prediction. To test the model prediction we
inhibited Apelin signaling in our model and in an \emph{in vitro} model of
angiogenic sprouting, and found that in both cases inhibition of Apelin or of
its receptor APJ reduces sprouting. Based on the prediction of the
computational model, we propose that the differential expression of Apelin and
APJ yields a "self-generated" gradient mechanisms that accelerates the
extension of the sprout.Comment: 48 pages, 10 figures, 8 supplementary figures. Accepted for
publication in PLoS ON
In vivo imaging of the tonoplast intrinsic protein family in Arabidopsis roots
Background: Tonoplast intrinsic proteins (TIPs) are widely used as markers for vacuolar
compartments in higher plants. Ten TIP isoforms are encoded by the Arabidopsis genome. For
several isoforms, the tissue and cell specific pattern of expression are not known.
Results: We generated fluorescent protein fusions to the genomic sequences of all members of
the Arabidopsis TIP family whose expression is predicted to occur in root tissues (TIP1;1 and 1;2;
TIP2;1, 2;2 and 2;3; TIP4;1) and expressed these fusions, both individually and in selected pairwise
combinations, in transgenic Arabidopsis. Analysis by confocal microscopy revealed that TIP
distribution varied between different cell layers within the root axis, with extensive co-expression
of some TIPs and more restricted expression patterns for other isoforms. TIP isoforms whose
expression overlapped appeared to localise to the tonoplast of the central vacuole, vacuolar bulbs
and smaller, uncharacterised structures.
Conclusion: We have produced a comprehensive atlas of TIP expression in Arabidopsis roots,
which reveals novel expression patterns for not previously studied TIPs
discrimination of different serbian pronunciations from shtokavian dialect
Abstract This paper proposes a new methodology for discrimination of different pronunciations in the Shtokavian dialect of the Serbian language. At the first, the written language (Unicode text) is converted into codes according to the energy status of each character in the text-line. Such a set of codes is seen as a grayscale image. Then, the local structures of the image are explored by local binary operators. It creates a vector set which differentiates various pronunciations of the Serbian language. The experiment is performed on fifty documents given in Serbian language. A comparison performed between the proposed method and the n -gram method shows its clear advantage
High-throughput simulation studies of angiogenesis : reverse engineering the role of tip cells and pericytes in vascular development
Angiogenesis is the process by which new blood vessels develop by splitting of or by sprouting from existing vessels. In sprouting angiogenesis vessels branch out and connect with other sprouts to form a new network. This process involves both the endothelial cells, which make up the inner lining of a vessel, and the perivascular cells, which surround the vessel. The collective behavior of these cells results in the formation of sprouts and eventually vascular networks. The cells involved in angiogenesis differ in shape and behavior, which affects their collective behavior. Furthermore, the cells also affect one another via diffusive and membrane bound signaling molecules. In this thesis we aim to understand how interactions between multiple cell-types exhibiting subtle differences in behavior change the resulting collective angiogenic sprouting. To this end, we developed cell-based, computational models of angiogenesis, based on the cellular Potts model. The inputs of these models are the observed or hypothesized behavior of individual cells and the output is the resulting collective cell behavior: e.g., the formation of angiogenic sprouts or vascular networks. By assigning different behavior to a subset of the cells, these models can be used to study the interplay between cell types exhibiting different behavior.Centrum Wiskunde & Informatica Netherlands Consortium for Systems BiologyUBL - phd migration 201
Neural Connectivity with Hidden Gaussian Graphical State-Model
The noninvasive procedures for neural connectivity are under questioning.
Theoretical models sustain that the electromagnetic field registered at
external sensors is elicited by currents at neural space. Nevertheless, what we
observe at the sensor space is a superposition of projected fields, from the
whole gray-matter. This is the reason for a major pitfall of noninvasive
Electrophysiology methods: distorted reconstruction of neural activity and its
connectivity or leakage. It has been proven that current methods produce
incorrect connectomes. Somewhat related to the incorrect connectivity
modelling, they disregard either Systems Theory and Bayesian Information
Theory. We introduce a new formalism that attains for it, Hidden Gaussian
Graphical State-Model (HIGGS). A neural Gaussian Graphical Model (GGM) hidden
by the observation equation of Magneto-encephalographic (MEEG) signals. HIGGS
is equivalent to a frequency domain Linear State Space Model (LSSM) but with
sparse connectivity prior. The mathematical contribution here is the theory for
high-dimensional and frequency-domain HIGGS solvers. We demonstrate that HIGGS
can attenuate the leakage effect in the most critical case: the distortion EEG
signal due to head volume conduction heterogeneities. Its application in EEG is
illustrated with retrieved connectivity patterns from human Steady State Visual
Evoked Potentials (SSVEP). We provide for the first time confirmatory evidence
for noninvasive procedures of neural connectivity: concurrent EEG and
Electrocorticography (ECoG) recordings on monkey. Open source packages are
freely available online, to reproduce the results presented in this paper and
to analyze external MEEG databases
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