878 research outputs found
Predictive response-relevant clustering of expression data provides insights into disease processes
This article describes and illustrates a novel method of microarray data analysis that couples model-based clustering and binary classification to form clusters of ;response-relevant' genes; that is, genes that are informative when discriminating between the different values of the response. Predictions are subsequently made using an appropriate statistical summary of each gene cluster, which we call the ;meta-covariate' representation of the cluster, in a probit regression model. We first illustrate this method by analysing a leukaemia expression dataset, before focusing closely on the meta-covariate analysis of a renal gene expression dataset in a rat model of salt-sensitive hypertension. We explore the biological insights provided by our analysis of these data. In particular, we identify a highly influential cluster of 13 genes-including three transcription factors (Arntl, Bhlhe41 and Npas2)-that is implicated as being protective against hypertension in response to increased dietary sodium. Functional and canonical pathway analysis of this cluster using Ingenuity Pathway Analysis implicated transcriptional activation and circadian rhythm signalling, respectively. Although we illustrate our method using only expression data, the method is applicable to any high-dimensional datasets
Induction of Cytotoxic T Lymphocyte Antigen 4 (Ctla-4) Restricts Clonal Expansion of Helper T Cells
Cytotoxic T lymphocyte antigen (CTLA)-4 plays an essential role in immunologic homeostasis. How this negative regulator of T cell activation executes its functions has remained controversial. We now provide evidence that CTLA-4 mediates a cell-intrinsic counterbalance to restrict the clonal expansion of proliferating CD4+ T cells. The regulation of CTLA-4 expression and function ensures that, after âŒ3 cell divisions of expansion, most progeny will succumb to either proliferative arrest or death over the ensuing three cell divisions. The quantitative precision of the counterbalance hinges on the graded, time-independent induction of CTLA-4 expression during the first three cell divisions. In contrast to the limits imposed on unpolarized cells, T helper type 1 (Th1) and Th2 effector progeny may be rescued from proliferative arrest by interleukin (IL)-12 and IL-4 signaling, respectively, allowing appropriately stimulated progeny to proceed to the stage of tissue homing. These results suggest that the cell-autonomous regulation of CTLA-4 induction may be a central checkpoint of clonal expansion of CD4+ T cells, allowing temporally and spatially restricted growth of progeny to be dictated by the nature of the threat posed to the host
Filtering Genes for Cluster and Network Analysis
<p>Abstract</p> <p>Background</p> <p>Prior to cluster analysis or genetic network analysis it is customary to filter, or remove genes considered to be irrelevant from the set of genes to be analyzed. Often genes whose variation across samples is less than an arbitrary threshold value are deleted. This can improve interpretability and reduce bias.</p> <p>Results</p> <p>This paper introduces modular models for representing network structure in order to study the relative effects of different filtering methods. We show that cluster analysis and principal components are strongly affected by filtering. Filtering methods intended specifically for cluster and network analysis are introduced and compared by simulating modular networks with known statistical properties. To study more realistic situations, we analyze simulated "real" data based on well-characterized E. coli and S. cerevisiae regulatory networks.</p> <p>Conclusion</p> <p>The methods introduced apply very generally, to any similarity matrix describing gene expression. One of the proposed methods, SUMCOV, performed well for all models simulated.</p
Radioactive 26Al and massive stars in the Galaxy
Gamma-rays from radioactive 26Al (half life ~7.2 10^5 yr) provide a
'snapshot' view of ongoing nucleosynthesis in the Galaxy. The Galaxy is
relatively transparent to such gamma-rays, and emission has been found
concentrated along the plane of the Galaxy. This led to the conclusion1 that
massive stars throughout the Galaxy dominate the production of 26Al. On the
other hand, meteoritic data show locally-produced 26Al, perhaps from spallation
reactions in the protosolar disk. Furthermore, prominent gamma-ray emission
from the Cygnus region suggests that a substantial fraction of Galactic 26Al
could originate in localized star-forming regions. Here we report high spectral
resolution measurements of 26Al emission at 1808.65 keV, which demonstrate that
the 26Al source regions corotate with the Galaxy, supporting its Galaxy-wide
origin. We determine a present-day equilibrium mass of 2.8 (+/-0.8) M_sol of
26Al. We use this to estimate that the frequency of core collapse (i.e. type
Ib/c and type II) supernovae to be 1.9(+/- 1.1) events per century.Comment: accepted for publication in Nature, 24 pages including Online
Supplements, 11 figures, 1 tabl
Destruction of density-wave states by a pseudo-gap in high magnetic fields: application to (TMTSF)ClO
A model is presented for the destruction of density-wave states in
quasi-one-dimensional crystals by high magnetic fields. The model is consistent
with previously unexplained properties of the organic conductors
(TMTSF)ClO and (BEDT-TTF)MHg(SCN) (M=K,Rb,Tl). As the magnetic
field increases quasi-one-dimensional density-wave fluctuations increase,
producing a pseudo-gap in the electronic density of states near the transition
temperature. When the pseudo-gap becomes larger than the mean-field transition
temperature formation of a density-wave state is not possible.Comment: 4 pages, RevTeX, 2 figures in uuencoded compressed tar file. Small
changes to text and Figure 1. Final version to appear in Physical Review
Letter
Ferromagnetic semiconductors
The current status and prospects of research on ferromagnetism in
semiconductors are reviewed. The question of the origin of ferromagnetism in
europium chalcogenides, chromium spinels and, particularly, in diluted magnetic
semiconductors is addressed. The nature of electronic states derived from 3d of
magnetic impurities is discussed in some details. Results of a quantitative
comparison between experimental and theoretical results, notably for Mn-based
III-V and II-VI compounds, are presented. This comparison demonstrates that the
current theory of the exchange interactions mediated by holes in the valence
band describes correctly the values of Curie temperatures T_C magnetic
anisotropy, domain structure, and magnetic circular dichroism. On this basis,
chemical trends are examined and show to lead to the prediction of
semiconductor systems with T_C that may exceed room temperature, an expectation
that are being confirmed by recent findings. Results for materials containing
magnetic ions other than Mn are also presented emphasizing that the double
exchange involving hoping through d states may operate in those systems.Comment: 18 pages, 8 figures; special issue of Semicon. Sci. Technol. on
semiconductor spintronic
The unexpected resurgence of Weyl geometry in late 20-th century physics
Weyl's original scale geometry of 1918 ("purely infinitesimal geometry") was
withdrawn by its author from physical theorizing in the early 1920s. It had a
comeback in the last third of the 20th century in different contexts: scalar
tensor theories of gravity, foundations of gravity, foundations of quantum
mechanics, elementary particle physics, and cosmology. It seems that Weyl
geometry continues to offer an open research potential for the foundations of
physics even after the turn to the new millennium.Comment: Completely rewritten conference paper 'Beyond Einstein', Mainz Sep
2008. Preprint ELHC (Epistemology of the LHC) 2017-02, 92 pages, 1 figur
Global 30â240 keV proton precipitation in the 17â18 April 2002 geomagnetic storms: 1. Patterns
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95215/1/jgra18503.pd
Statistical Multifragmentation of Non-Spherical Expanding Sources in Central Heavy-Ion Collisions
We study the anisotropy effects measured with INDRA at GSI in central
collisions of Xe+Sn at 50 A.MeV and Au+Au at 60, 80, 100 A.MeV incident energy.
The microcanonical multifragmentation model with non-spherical sources is used
to simulate an incomplete shape relaxation of the multifragmenting system. This
model is employed to interpret observed anisotropic distributions in the
fragment size and mean kinetic energy. The data can be well reproduced if an
expanding prolate source aligned along the beam direction is assumed. An either
non-Hubblean or non-isotropic radial expansion is required to describe the
fragment kinetic energies and their anisotropy. The qualitative similarity of
the results for the studied reactions suggests that the concept of a
longitudinally elongated freeze-out configuration is generally applicable for
central collisions of heavy systems. The deformation decreases slightly with
increasing beam energy.Comment: 35 pages, 19 figures, submitted to Nuclear Physics
Multiomics profiling of primary lung cancers and distant metastases reveals immunosuppression as a common characteristic of tumor cells with metastatic plasticity
BACKGROUND: Metastasis is the primary cause of cancer mortality accounting for 90% of cancer deaths. Our understanding of the molecular mechanisms driving metastasis is rudimentary. RESULTS: We perform whole exome sequencing (WES), RNA sequencing, methylation microarray, and immunohistochemistry (IHC) on 8 pairs of non-small cell lung cancer (NSCLC) primary tumors and matched distant metastases. Furthermore, we analyze published WES data from 35 primary NSCLC and metastasis pairs, and transcriptomic data from 4 autopsy cases with metastatic NSCLC and one metastatic lung cancer mouse model. The majority of somatic mutations are shared between primary tumors and paired distant metastases although mutational signatures suggest different mutagenesis processes in play before and after metastatic spread. Subclonal analysis reveals evidence of monoclonal seeding in 41 of 42 patients. Pathway analysis of transcriptomic data reveals that downregulated pathways in metastases are mainly immune-related. Further deconvolution analysis reveals significantly lower infiltration of various immune cell types in metastases with the exception of CD4+ T cells and M2 macrophages. These results are in line with lower densities of immune cells and higher CD4/CD8 ratios in metastases shown by IHC. Analysis of transcriptomic data from autopsy cases and animal models confirms that immunosuppression is also present in extracranial metastases. Significantly higher somatic copy number aberration and allelic imbalance burdens are identified in metastases. CONCLUSIONS: Metastasis is a molecularly late event, and immunosuppression driven by different molecular events, including somatic copy number aberration, may be a common characteristic of tumors with metastatic plasticity
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